MOLECULAR IMAGING IN THE PRECISION MEDICINE ERACHALLENGES AND PERSPECTIVES

Figure 1111b The Biology of Cancer (copy Garland Science 2007)

ONE CELL OF ORIGIN MULTIPLE GENOTYPES WITHIN THE VERY SAME CANCER

(and I think different molecular diseases just affecting the same organ)

GENETIC INTRATUMOR HETEROGENEITY AND PHYLOGENY IN PATIENT

Gerlinger M et al N Engl J Med 2012366883-892

CORRELATIONS BETWEEN GENOTYPE AND PHENOTYPE IN PATIENT 1

Gerlinger M et al N Engl J Med 2012366883-892

Mutation landscapes of individual tumorsand the prediction of driver mutations in cancers

Umbrella and Basket trialstreating mutations nor tumors (hellipnor patients)

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Figure 1111b The Biology of Cancer (copy Garland Science 2007)

ONE CELL OF ORIGIN MULTIPLE GENOTYPES WITHIN THE VERY SAME CANCER

(and I think different molecular diseases just affecting the same organ)

GENETIC INTRATUMOR HETEROGENEITY AND PHYLOGENY IN PATIENT

Gerlinger M et al N Engl J Med 2012366883-892

CORRELATIONS BETWEEN GENOTYPE AND PHENOTYPE IN PATIENT 1

Gerlinger M et al N Engl J Med 2012366883-892

Mutation landscapes of individual tumorsand the prediction of driver mutations in cancers

Umbrella and Basket trialstreating mutations nor tumors (hellipnor patients)

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

GENETIC INTRATUMOR HETEROGENEITY AND PHYLOGENY IN PATIENT

Gerlinger M et al N Engl J Med 2012366883-892

CORRELATIONS BETWEEN GENOTYPE AND PHENOTYPE IN PATIENT 1

Gerlinger M et al N Engl J Med 2012366883-892

Mutation landscapes of individual tumorsand the prediction of driver mutations in cancers

Umbrella and Basket trialstreating mutations nor tumors (hellipnor patients)

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

CORRELATIONS BETWEEN GENOTYPE AND PHENOTYPE IN PATIENT 1

Gerlinger M et al N Engl J Med 2012366883-892

Mutation landscapes of individual tumorsand the prediction of driver mutations in cancers

Umbrella and Basket trialstreating mutations nor tumors (hellipnor patients)

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Mutation landscapes of individual tumorsand the prediction of driver mutations in cancers

Umbrella and Basket trialstreating mutations nor tumors (hellipnor patients)

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Umbrella and Basket trialstreating mutations nor tumors (hellipnor patients)

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Vemurafenib

RAS

BRAFV600E

BRAF(wt)

MEK

ERK

Gene Transcription

RAF1PI3KAKT

Apoptosis

PTEN

bull Inhibits BRAF Activity

bull BRAF-V600E Mutants are

specially sensitive to blocking

of BRAF activity

bull Moderate Toxicity (Targeted)

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Clinical Trial

bull Phase II trial

bull Patients received Vemurafenib twice daily until disease progression

bull 49 Melanoma patients

Flaherty et al 2010 N Eng J Med 3639

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Gatenby Silva 2009 Cancer Res 2009 69 4894-4903

Smalley et al N Engl J Med 2010 3639

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

pt19

pt18

pt14

pt12

pt11

pt10

pt9

pt8

pt7

pt6

pt5

pt4

pt3

70

Hokanson Et al 1977 Cancer 391077-1084

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Months

Patient Treatment Response Regression

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

12

S RBRAFi

BRAFi sensitive BRAFi resistant

PLASTICITY TO SENSITIVITY

DOSE SCHEDULING

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

13

continuous drug exposure

S RBRAFi

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

14

2 weeks on - 2 weeks off

4 weeks on - 2 weeks off 4 weeks on - 4 weeks off

3 weeks on - 3 weeks off

Scheduling affects tumor volume until resistant cells take over

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

15

S R S R

S RS R

BRAFi BRAFi

Drug + sensitizer works better simultaneously

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Summary Ibull Cancers are moving targets due to their genomic

instabilitybull Next generation sequencing allows to determine key driver

mutations in cancershellipbull hellipwhich are potentially heterogeneous in the very same

patient (design of umbrella trials- II)bull Targeted therapies are designed to target mutated

genotypes that may be shared by different cancer types (design of basket trials)

bull There is a need to develop real time diagnosis of the population dynamics within any given cancer patient in a minimally invasive manner to orient treatment regimens and possible drug combinations development of liquid biopsies

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

ANGIOGENESIS AND VASCULAR FUNCTION CONTROL IN EXPERIMENTAL TUMORS

Vasoactive peptides and their angiogenicvascular permeability functions

Angiotensin II antagonists and bradykinin antagonism

Imag(in)ing tumor vasculature function and interfering withtumor perfusion

IMAG(IN)ING THE TUMOR MICROENVIRONMENT IN EXPERIMENTAL MELANOMA

MODELS

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

TUMOR VASCULARIZATION AND ANGIOGENESIS

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxipeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increase vascular tonusDecrease vascular tonus

Losartan candesartan

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

PRESENCE OF AT1 RECEPTORS AND ANGIOTENSIN II IN HUMAN MELANOMA TISSUES

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

ANGIOTENSIN II ANTAGONISTS LIMITED MURINE MELANOMA GROWTH

Otake et al(2010) Cancer Chemother Pharmacol 6679-87Maximal tolerated dose of Losartan

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

MICROVASCULAR DENSITY (MVD) WAS DECREASED UPON LOS TREATMENT

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Otake et al(2010) Cancer Chemother Pharmacol 6679-87

LOSARTAN INTERFERED WITH THE RECRUITMENT OF VEGFR2 POSITIVE CELLS

TO TUMORS

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Low dose of losartan

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

NAT COMMUN 201342516 DOI 101038NCOMMS3516

ANGIOTENSIN INHIBITION ENHANCES DRUG DELIVERY AND POTENTIATES

CHEMOTHERAPY BY DECOMPRESSING TUMOUR BLOOD VESSELSCHAUHAN VP1 MARTIN JD LIU H LACORRE DA JAIN SR KOZIN SV STYLIANOPOULOS T MOUSA AS HAN X ADSTAMONGKONKUL

P POPOVIĆ ZHUANG P BAWENDI MG BOUCHER Y JAIN RK

Angiotensin I

Angiotensin II

AT1R

Bradykinin

Inactive

peptides

B2R

Angiotensinogen

Renin

Kininogen

Kallikreins

ACE

AT2R

des-Arg9

-

Bradykinin

B1R

Carboxypeptidases

ANGIOTENSIN II BRADYKININ AND DES-ARG-BRADYKININ CONTROL THE VASCULAR

TONUS AND OTHER ENDOTHELIAL CELL FUNCTIONS ANGIOTENSIN CONVERTING

ENZYME (ACE) CONNECTS BOTH SYSTEMS

Increases vascular tonusDecrease vascular tonus

R-715 R-954

Induces angiogenesisIncrease vascular permeability

CD31Doxorubicin

PBS

R-954

THE BKR1 ANTAGONISTS R715 AND R954 INCREASED DOXORUBICIN UPTAKE

WITHIN TUMORS

US2007015715-A1 Nantel et al Derwent Innovations Index 2007-239159

Costa el al (2014) Cancer Lett 345 27-38

adverse effects of R954R715 include a transient increase in blood pressure

THE BKR1 ANTAGONIST R715 IMPROVED THE EFFICACY OF DACARBAZINE (DCB) IN MURINE MELANOMAS

CTL DCB R715 R715+DCB000

005

010

015

020

025

030

035

Mas

sa t

um

ora

l (g

)Tu

mo

r m

ass

(g)

LNS Andrade

MRI STUDIES OPEN THE PERSPECTIVE OF EVALUATING DIFFERENT VARIABLES OF

TUMOR PHYSIOLOGY

Chammas et al in preparation

SUCH AS DIFFUSION OF CONTRASTING AGENTS WITHIN THE TUMOR AS A PROXY

OF TUMOR PERFUSION

Rela

tive

Inte

nsit

y

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

CD31Doxorubicin

PBS

R-954

THE BKR1 ANTAGONISTS R715 AND R954 INCREASED DOXORUBICIN UPTAKE

WITHIN TUMORS

US2007015715-A1 Nantel et al Derwent Innovations Index 2007-239159

Costa el al (2014) Cancer Lett 345 27-38

adverse effects of R954R715 include a transient increase in blood pressure

THE BKR1 ANTAGONIST R715 IMPROVED THE EFFICACY OF DACARBAZINE (DCB) IN MURINE MELANOMAS

CTL DCB R715 R715+DCB000

005

010

015

020

025

030

035

Mas

sa t

um

ora

l (g

)Tu

mo

r m

ass

(g)

LNS Andrade

MRI STUDIES OPEN THE PERSPECTIVE OF EVALUATING DIFFERENT VARIABLES OF

TUMOR PHYSIOLOGY

Chammas et al in preparation

SUCH AS DIFFUSION OF CONTRASTING AGENTS WITHIN THE TUMOR AS A PROXY

OF TUMOR PERFUSION

Rela

tive

Inte

nsit

y

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

THE BKR1 ANTAGONIST R715 IMPROVED THE EFFICACY OF DACARBAZINE (DCB) IN MURINE MELANOMAS

CTL DCB R715 R715+DCB000

005

010

015

020

025

030

035

Mas

sa t

um

ora

l (g

)Tu

mo

r m

ass

(g)

LNS Andrade

MRI STUDIES OPEN THE PERSPECTIVE OF EVALUATING DIFFERENT VARIABLES OF

TUMOR PHYSIOLOGY

Chammas et al in preparation

SUCH AS DIFFUSION OF CONTRASTING AGENTS WITHIN THE TUMOR AS A PROXY

OF TUMOR PERFUSION

Rela

tive

Inte

nsit

y

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

MRI STUDIES OPEN THE PERSPECTIVE OF EVALUATING DIFFERENT VARIABLES OF

TUMOR PHYSIOLOGY

Chammas et al in preparation

SUCH AS DIFFUSION OF CONTRASTING AGENTS WITHIN THE TUMOR AS A PROXY

OF TUMOR PERFUSION

Rela

tive

Inte

nsit

y

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

SUCH AS DIFFUSION OF CONTRASTING AGENTS WITHIN THE TUMOR AS A PROXY

OF TUMOR PERFUSION

Rela

tive

Inte

nsit

y

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

Chammas et al in preparation

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

Chammas et al in preparation

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

Chammas et al in preparation

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

0 5 10 15

100

125

150

175

200

225

Injection

Before

ITS

HTS 375

mannitol

HTS 75

Minutes after intravenous injection

Do

pp

ler

ve

locity (

)

B16-F10 melanoma

DOPPLER STUDIES

Chammas et al in preparation

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery

SUMMARY

Both angiotensin II and its receptor (AT1) are present within the tumormicroenvironment of human melanomas and murine melanomas

The antihypertensive agent Losartan has a dual function controlling not onlythe vascular tonus but also controlling angiogenesis

Off label indications of old drugs (Losartan eg) may help managing cancerpatients

Opportunity for an academic clinical trial

Bradykinin receptor 1 antagonists may lead to secondary local and transienthypertension favouring drug delivery to experimental tumors Transient increase in tumor perfusion can also be induced through usage of hypertonic saline solutions

Multimodality imaging allowed for devising a strategy of combination therapy to improve drug delivery