Pancreatic Cancer Research

Pipeline of New Treatment Options Derek W Louden MA (Abdn) MA (Shef) MEI

Tel 07876 774412

Email LoudenDWaolcom

William Louden (1936-2016)

Rest In Peace Dad

WARNING

Irsquom not a doctor I have had no medical training

Irsquove written this PowerPoint for people with pancreatic cancer and for their family members who will do what I did and spend months trying to find a cure for my father My intention is to help you by pointing out a few places to look

I found some things which work with standard chemo regimes Talk to your doctor oncologist prior to trying any of them If they say ldquonordquo listen

I also found some things which were tantalisingly close to being available They could be available now You should also look for developments after I stopped looking in May 2016 I wish every one of you the very best of luck

Pancreatic Cancer has one of the worst prognoses of any cancer The survival times havenrsquot improved much in 40 years

Pancreatic Cancer Grows

Tumours grow within and around vital organs

Pancreatic Cancer Spreads

Cancer cells detach from the original tumour and migrate via a process known as Metastasis (Mets) to other sites around the body Current treatment can delay but isnrsquot able to prevent Mets

httpwwwpathpediacomeducationeatlashistopathologypancreasductal_adenocarcinoma_nospancreatic-ductal-adenocarcinoma-5B3-pn004_15DjpegWidth=600ampHeight=450ampFormat=4

WARNING

Irsquom not a doctor I have had no medical training

Irsquove written this PowerPoint for people with pancreatic cancer and for their family members who will do what I did and spend months trying to find a cure for my father My intention is to help you by pointing out a few places to look

I found some things which work with standard chemo regimes Talk to your doctor oncologist prior to trying any of them If they say ldquonordquo listen

I also found some things which were tantalisingly close to being available They could be available now You should also look for developments after I stopped looking in May 2016 I wish every one of you the very best of luck

Pancreatic Cancer has one of the worst prognoses of any cancer The survival times havenrsquot improved much in 40 years

Pancreatic Cancer Grows

Tumours grow within and around vital organs

Pancreatic Cancer Spreads

Cancer cells detach from the original tumour and migrate via a process known as Metastasis (Mets) to other sites around the body Current treatment can delay but isnrsquot able to prevent Mets

httpwwwpathpediacomeducationeatlashistopathologypancreasductal_adenocarcinoma_nospancreatic-ductal-adenocarcinoma-5B3-pn004_15DjpegWidth=600ampHeight=450ampFormat=4

Pancreatic Cancer has one of the worst prognoses of any cancer The survival times havenrsquot improved much in 40 years

Pancreatic Cancer Grows

Tumours grow within and around vital organs

Pancreatic Cancer Spreads

Cancer cells detach from the original tumour and migrate via a process known as Metastasis (Mets) to other sites around the body Current treatment can delay but isnrsquot able to prevent Mets

httpwwwpathpediacomeducationeatlashistopathologypancreasductal_adenocarcinoma_nospancreatic-ductal-adenocarcinoma-5B3-pn004_15DjpegWidth=600ampHeight=450ampFormat=4

Current Research for Improved Survival Rates

Wersquoll Look at the Following clinical studies

Metformin ndash not recommended siG12D-LODER releases siRNA to knock down YAP1 miR-375 to target 3rsquoUTR of YAP1 mRNA Snail regulated miR-375 targeting JAK2 Peptide Mimicking VGLL4 PEGPH20 ablates Stromal HA QD232 Targeting SrcFAK and STAT3 signalling Cilengitide amp Verapamil combination therapy with Gemcitabine C19 Small Molecule inhibitor of Hippo TGF-B and Wnt Vitamin D Receptor-Mediated Stromal Reprogramming THERACURMINreg (Curcumin) Minnelide (Triptolide) Salinomycin Protein Kinase D1 QS molecule O-DDHSL interleukin-10 (IL-10) gene

And new Delivery Method

Polymeric Micelles for Salinomycin delivery

Metformin

Metformin

Theory Metformin would use its antineoplastic properties to target the Stroma to ablate this physical barrier to Chemo extending survival time for patients Result A recent study in The Lancet showed Metformin did not improve the survival prospects of patients with advanced pancreatic cancer Indeed 639 of the placebo group on Gemcitabine and Erlotinib survived 6 months whereas only 567 of the group given Metformin along with Gemcitabine and Erlotinib were still alive

Metformin

Metformin

Results showed Epithelial-Mesenchymal Transition isnrsquot slowed

Source ldquoEpithelialndashmesenchymal plasticity in carcinoma metastasisrdquo Jeff H Tsai and Jing Yang Department of Pharmacology Department of Pediatrics School of Medicine University of California at San Diego La Jolla California 92093 USA httpgenesdevcshlporgcontent27202192fullpdf+html

Metformin

Metformin

Theory Metformin would use its antineoplastic properties to target the Stroma to ablate this physical barrier to Chemo extending survival time for patients Result A recent study in The Lancet showed Metformin did not improve the survival prospects of patients with advanced pancreatic cancer Indeed 639 of the placebo group on Gemcitabine and Erlotinib survived 6 months whereas only 567 of the group given Metformin along with Gemcitabine and Erlotinib were still alive

Metformin

Metformin

Results showed Epithelial-Mesenchymal Transition isnrsquot slowed

Source ldquoEpithelialndashmesenchymal plasticity in carcinoma metastasisrdquo Jeff H Tsai and Jing Yang Department of Pharmacology Department of Pediatrics School of Medicine University of California at San Diego La Jolla California 92093 USA httpgenesdevcshlporgcontent27202192fullpdf+html

Metformin

Metformin

Results showed Epithelial-Mesenchymal Transition isnrsquot slowed

Source ldquoEpithelialndashmesenchymal plasticity in carcinoma metastasisrdquo Jeff H Tsai and Jing Yang Department of Pharmacology Department of Pediatrics School of Medicine University of California at San Diego La Jolla California 92093 USA httpgenesdevcshlporgcontent27202192fullpdf+html

Metformin

Metformin

Conclusion Metformin was thought to protect patients by allowing Chemo to get through the stroma to attack the Cancer What seems to have happened is that the process of weakening the stroma has the result of allowing the latter stages of Cancer progression to proceed faster than the Gemcitabine can counteract it This suggests that badly damaging the stroma isnrsquot a good idea as the stroma acts to protect the patient from the invasion of metastatic cancer An alternative method is needed to get the Gemcitabine past the stroma without so weakening it as to leave it open to metastatic attack

Suppressing YAP and the p53 oncogene

Pancreatic Cancer - Suppressing YAP and the p53 oncogene

Gene Therapy for Pancreatic Tumours A team at Georgetown Lombardi Comprehensive Cancer Center in Washington led by Prof W Zhang and Associate Prof Chunling Yi has published a study showing that inhibiting a single protein completely shuts down growth of Pancreatic Cancer httpwwwncbinlmnihgovpmcarticlesPMC4175524 httpwwwncbinlmnihgovpubmed24803537 Around 95 of patients are found to have a KRAS gene mutation and 75 have a P53 gene mutation Suppressing a protein known as YAP didnrsquot stop the cancer developing but it did stop it progressing Suppressing YAP also shuts down the activity of the p53 oncogene

Schematic of the function of YAP in PDAC cells as a master transcriptional switch of the KRAS secre-tome promoting PDAC cell proliferation

Downstream of Mutant KRAS the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma Weiying Zhang Nivedita Nandakumar Yuhao Shi Mark Manzano Alias Smith Garrett Graham Swati Gupta Eveline E Vietsch Sean Z Laughlin Mandheer Wadhwa Mahandranauth Chetram Mrinmayi Joshi Fen Wang Bhaskar Kallakury Jeffrey Toretsky Anton Wellstein and Chunling Yi Sci Signal 7(324) ra42 doi101126scisignal2005049 wwwsciencesignalingorgcgicontentfull7324ra42DC1 Correspondence cy232georgetownedu

Suppressing YAP and the p53 oncogene

Pancreatic Cancer - Suppressing YAP and the p53 oncogene

Gene Therapy for Pancreatic Tumours A team at Georgetown Lombardi Comprehensive Cancer Center in Washington led by Prof W Zhang and Associate Prof Chunling Yi has published a study showing that inhibiting a single protein completely shuts down growth of Pancreatic Cancer httpwwwncbinlmnihgovpmcarticlesPMC4175524 httpwwwncbinlmnihgovpubmed24803537 Around 95 of patients are found to have a KRAS gene mutation and 75 have a P53 gene mutation Suppressing a protein known as YAP didnrsquot stop the cancer developing but it did stop it progressing Suppressing YAP also shuts down the activity of the p53 oncogene

Schematic of the function of YAP in PDAC cells as a master transcriptional switch of the KRAS secre-tome promoting PDAC cell proliferation

Downstream of Mutant KRAS the Transcription Regulator YAP Is Essential for Neoplastic Progression to Pancreatic Ductal Adenocarcinoma Weiying Zhang Nivedita Nandakumar Yuhao Shi Mark Manzano Alias Smith Garrett Graham Swati Gupta Eveline E Vietsch Sean Z Laughlin Mandheer Wadhwa Mahandranauth Chetram Mrinmayi Joshi Fen Wang Bhaskar Kallakury Jeffrey Toretsky Anton Wellstein and Chunling Yi Sci Signal 7(324) ra42 doi101126scisignal2005049 wwwsciencesignalingorgcgicontentfull7324ra42DC1 Correspondence cy232georgetownedu

siG12D-LODER

siG12D-LODERtrade Biodegradable implant

Theory A siRNA drug would be used against KRAS(G12D) which is subject to a genetic mutation in 90 of Pancreatic Ductal Adenocarcinoma cases Action A miniature biodegradable implant siG12D-LODERtrade was inserted into a tumour and released a siRNA drug against KRAS(G12D) over four months Result Patient survival times were significantly improved

httpwwwimpactjournalscomoncotargetindexphpjournal=oncotargetamppage=articleampop=viewamppath[]=4183 Talia Golan email TaliaGolanshebahealthgovil

What current research is there

Pancreatic Cancer - miR-375

Gene Therapy for Pancreatic Tumours - miR-375 A team from the Laboratory of Animal Development Biology College of Life Science Northeast Forestry University Hexing Road Harbin China under ZW Zhang found that YAP1 was highly expressed in embryonic and adult pancreatic progenitor cells Knocking down YAP1 by siRNA inhibited the proliferation of pancreatic progenitor cells miR-375 targeted the 3 UTR of YAP1 mRNA to decrease its protein and mRNA levels Similar to silencing YAP1 by siRNA the proliferation of pancreatic progenitor cells was inhibited significantly by miR-375

miR-375 Inhibits Proliferation of Mouse Pancreatic Progenitor Cells by Targeting YAP1 Zhang Z-W middot Men T middot Feng R-C middot Li Y-C middot Zhou D middot Teng C-B Cell Physiol Biochem 2013321808-1817 (DOI101159000356614) Chun-Bo Teng Laboratory of Animal Development Biology College of Life Science Northeast Forestry University No26 Hexing Road Harbin 150040 (China) Fax +86-451 -82191784 E-Mail chunbotengnefueducn httpwwwkargercomArticleFullText356614 httpwwwncbinlmnihgovpubmed24356001

miR-375 to target 3rsquoUTR of YAP1 mRNA

Pancreatic Cancer - miR-375

miR-375 miR-375 works like siRNA to inhibit the proliferation of pancreatic progenitor cells ndash or cancer stem cells (CSCs)

httpsenwikipediaorgwikiMir-375

miR-375 has been found significantly downregulated in multiple types of cancer and suppresses core hallmarks of cancer by targeting several important oncogenes like AEG-1 YAP1 IGF1R and PDK1 Expression levels of JAK2 and miR-375 are inversely correlated in GC tissues ldquoThe Emerging Role of miR-375 in Cancerrdquo Jun-Wei Yan Ju-Sheng Lin and Xing-Xing H Int J Cancer 2014 Sep 1135(5)1011-8 doi 101002ijc28563 Epub 2013 Nov 13 httpwwwncbinlmnihgovpubmed24166096

miR-375 to target 3rsquoUTR of YAP1 mRNA

Pancreatic Cancer -

Gene Therapy for Pancreatic Tumours 3 MicroRNAs are being investigated by a team under Jun Wei Yan at the Institute of Liver Diseases Tongji Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China miR-375 is a multi-functional miRNA which is significantly downregulated in many types of cancer including pancreatic MiR-375 is significantly downregulated in multiple cancers and acts as a tumor suppressor by targeting important oncogenes such as AEG-1 PDK1 ATG7 IGF1R JAK2 14-3-3Z YAP1 and SP1 MiR-375 moderates cancer-related processes such as cell proliferation apoptosis invasion and migration metastasis and autophagy

ldquoThe Emerging Role of miR-375 in Cancerrdquo Jun-Wei Yan Ju-Sheng Lin and Xing-Xing He Int J Cancer 2014 Sep 1135(5)1011-8 doi 101002ijc28563 Epub 2013 Nov 13 httpwwwncbinlmnihgovpubmed24166096 E-mail xxhetjhtjmueducn or jslintjhtjmueducn

miR-375 to target 3rsquoUTR of YAP1 mRNA

Pancreatic Cancer - miR-375

ldquoThe Emerging Role of miR-375 in Cancerrdquo Jun-Wei Yan Ju-Sheng Lin and Xing-Xing He Int J Cancer 2014 Sep 1135(5)1011-8 doi 101002ijc28563 Epub 2013 Nov 13 httpwwwncbinlmnihgovpubmed24166096 E-mail xxhetjhtjmueducn or jslintjhtjmueducn

Snail-Regulated MiR-375 Inhibits Migration and Invasion of Gastric Cancer Cells by Targeting JAK2

Pancreatic Cancer - miR-375

A further study of miR-375 looked at how it prevents migration and invasion of Gastric Cancer Cells at least in part by targeting Janus Kinase 2 (JAK2) miR-375 is regulated by and inversely correlated with Snail mRNA Too much Snail means miR-375 can no longer suppress JAK2 which allows Gastric Cancer Cells to metastasise restoration of miR-375 or inhibition of Snail or JAK2 may be useful therapeutic strategies for gastric cancer treatment Xu Y Jin J Liu Y Huang Z Deng Y et al (2014) Snail-Regulated MiR-375 Inhibits Migration and Invasion of Gastric Cancer Cells by Targeting JAK2 PLoSONE 9(7) e99516 doi101371journalpone0099516 httpwwwncbinlmnihgovpmcarticlesPMC4108470

Peptide Mimicking VGLL4

Pancreatic Cancer - Peptide Mimicking VGLL4

Over-expression of YAP plays a key role in switching off defences against cancer and in allowing cancer cells to start to spread

The Hippo Pathway and YAPTAZndashTEAD ProteinndashProtein Interaction as Targets for Regenerative Medicine and Cancer Treatment Matteo Santucci Tatiana Vignudelli Stefania Ferrari Marco Mor Laura Scalvini Maria Laura Bolognesi Elisa Uliassi and Maria Paola Costi J Med Chem 2015 58 (12) pp 4857ndash4873 Publication Date (Web) February 26 2015 (Perspective) DOI 101021jm501615v

Peptide Mimicking VGLL4

Pancreatic Cancer - Peptide Mimicking VGLL4

The YAP TEAD interaction A Chinese team has looked at peptides and has developed one called Super-TDU which can mimick VGLL4 to compete with YAP for TEAD4 binding thus preventing over-expression of YAP causing metastasis Jiao S et al A peptide mimicking VGLL4 function acts as a YAP antagonist therapy against gastric cancer Cancer Cell 25 166ndash180 (2014) 101016jccr201401010 Correspondence hbjisibcbaccn (HJ) rayzhangsibcbaccn (LZ) zczhousibcbaccn (ZZ)

PEGPH20 ablates Stromal HA

Pancreatic Cancer - PEGPH20 ablates Stromal HA

PEGPH20 ablates Stromal HA Halozyme Theraputics has developed a treatment which is beneficial for patients who have high levels of hyaluronan (HA) PEGPH20 targets HA to help improve cancer therapy access to tumor cells HYLENEXreg recombinant human hyaluronidase Result In the 30 high HA patients who were evaluated for response prior to the April 2014 clinical hold and subsequent PEGPH20 treatment discontinuation the overall response rate was 73 percent Study was halted due to ldquoThromboembolic Eventsrdquo ndash strokes Now re-started

Sunil Hingorani MD PhD Click here to for pdf copy of the ASCO 2015 oral presentation

PEGPH20 ablates Stromal HA

Pancreatic Cancer - PEGPH20 ablates Stromal HA

PEGPH20 ablates Stromal HA Halozyme Theraputics has developed a treatment which is beneficial for patients who have high levels of hyaluronan (HA) PEGPH20 targets HA to help improve cancer therapy access to tumor cells HYLENEXreg recombinant human hyaluronidase Result In the 30 high HA patients who were evaluated for response prior to the April 2014 clinical hold and subsequent PEGPH20 treatment discontinuation the overall response rate was 73 percent Study was halted due to ldquoThromboembolic Eventsrdquo ndash strokes Now re-started

Sunil Hingorani MD PhD Click here to for pdf copy of the ASCO 2015 oral presentation

QD232 Targeting SrcFAK and STAT3 signalling

Pancreatic Cancer - QD232 Targeting SrcFAK and STAT3 signalling

QD232 Targeting SrcFAK and STAT3 signalling ndash Theory Simultaneously targeting SrcFAK and STAT3 signalling could provide an important strategy for treating pancreatic cancer Result QD232 potently inhibited SrcFAK and STAT3 phosphorylation decreasing pancreatic cancer cell viability and migration Furthermore QD232 arrested cell cycle progression and induced apoptosis in these cells at low micromolar concentrations

Pathania D Kuang Y Sechi M and Neamati N (2015) Mechanisms underlying the cytotoxicity of a novel quinazolinedione-based redox modulator QD232 in pancreatic cancer cells British Journal of Pharmacology 172 50ndash63 doi 101111bph12855 httponlinelibrarywileycomdoi101111bph12855abstractjsessionid=49F90EC6FF2EC5B8ED1D48EB82DE0C8Ef04t01 httpwwwncbinlmnihgovpubmed23954204 Email neamatiuscedu or neamatiumichedu or mariosechiunissit

Cilengitide amp Verapamil combination therapy with Gemcitabine

Pancreatic Cancer - Cilengitide amp Verapamil combination therapy with Gemcitabine

Theory Cilengitide amp Verapamil in combination with Gemcitabine might improve survival time Result Combination Therapy with all three was indeed the best option

Dual-Action Combination Therapy Enhances Angiogenesis while Reducing Tumor Growth and Spread Ping-Pui Wong Fevzi Demircioglu Essam Ghazaly Wasfi Alrawashdeh Michael RL Stratford Cheryl L Scudamore Biancastella Cereser Tatjana Crnogorac-Jurcevic Stuart McDonald George Elia Thorsten Hagemann Hemant M Kocher and Kairbaan M Hodivala-Dilke httpwwwncbinlmnihgovpubmed25584895 Correspondence khodivala-dilkeqmulacuk

C19 Small Molecule Inhibitor of Hippo TGF-B and Wnt

Pancreatic Cancer - C19 Small Molecule Inhibitor of Hippo TGF-B and Wnt

Small Molecule Inhibitor of Hippo TGF-B and Wnt A team at the University of Pittsburg including the inventor Abdelhadi Rebbaa has developed a compound C19 with a powerful inhibitory effect on Hippo Wnt and TGF-B Hadi is presently engaged in a funding round to build a Lab to continue his work on C19 this time in the clinic His patent application is in C19 inhibited tumour growth in a dose dependent manner with 20 mgkg inducing approx 90 inhibition

Identification Mechanism of Action and Antitumor Activity of a Small Molecule Inhibitor of Hippo TGF-b and Wnt Signaling Pathways Dipanjan Basu1 Robert Lettan3 Krishnan Damodaran2 Susan Strellec3 Miguel Reyes-Mugica1 and Abdelhadi Rebbaa1 httpmctaacrjournalsorgcontentearly201405221535-7163MCT-13-0918fullpdf E-mail abr25pittedu

Modified Vitamin D ndash Stromal reprogramming with Calcipotriol

Pancreatic Cancer -

Modified Vitamin D treatment for Pancreatic Cancer QMUL the vitamin D receptor (VDR) is expressed in stroma from human PDA tumours Treatment with the VDR ligand calcipotriol markedly reduced markers of inflammation and fibrosis in pancreatitis and human tumour stroma VDR acts as a master transcriptional regulator of PSCs to reprise the quiescent state resulting in induced stromal remodeling increased intratumoural gemcitabine reduced tumour volume and a 57 increase in survival versus chemo alone

Vitamin D Receptor-Mediated Stromal Reprogramming Suppresses Pancreatitis and Enhances Pancreatic Cancer Therapy Mara H Sherman Ruth T Yu Dannielle D Engle Ning Ding Annette R Atkins Herve Tiriac Eric A Collisson Frances Connor Terry Van Dyke Serguei Kozlov Philip Martin Tiffany W Tseng David W Dawson Timothy R Donahue Atsushi Masamune Tooru Shimosegawa Minoti V Apte Jeremy S Wilson Beverly Ng Sue Lynn Lau Jenny E Gunton Geoffrey M Wahl Tony Hunter Jeffrey A Drebin Peter J OrsquoDwyer Christopher Liddle David A Tuveson Michael Downes and Ronald M Evans1 httpwwwsciencedirectcomsciencearticlepiiS0092867414010332 Correspondence downessalkedu (MD) evanssalkedu (RME)

Curcumin Pancreatic Cancer - Combination treatment with Gemcitabine and Curcumin

Combination treatment with Gemcitabine and Curcumin A team from Ohio showed that this combination had a synergistic effect Curcumin has antioxidant and anti-inflammatory properties and has been shown to protect against carcinogenesis and prevent tumour formation and development in several types of cancer and also to suppress angiogenesis and metastasis in a variety of animal tumour models

Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells Lauren Friedman Li Lin Sarah Ball Tanios Bekaii-Saab James Fuchs Pui-Kai Li Chenglong Li and Jiayuh Lin Anticancer Drugs 2009 July 20(6) 444ndash449 doi101097CAD0b013e32832afc04 httpwwwncbinlmnihgovpubmed19384191 Correspondence to Jiayuh Lin PhD lin674osuedu

Due to poor bio-availability a concentrated form Theracurmin has been developed by a team in Japan

Curcumin and Pancreatic Cancer A Research and Clinical Update Carlos J Diacuteaz Osterman and Nathan R Wall Journal of Nature and Science 1(6)e124 2015Corresponding Author Nathan R Wall PhD httpwwwjnsciorgfileshtmle124htm Email nwalllluedu

Theracurmin Pancreatic Cancer - Combination treatment with Gemcitabine and Theracurmin

Combination treatment with Gemcitabine and Theracurmin A team from Kyoto University Hospital led by Masashi Kanai identified the potential theraputic benefits of curcumin They next set to work on improving the bio-availability of the agent by developing a concentrated version Theracurmin This has undergone clinical trials Result Repetitive systemic exposure to high concentrations of curcumin achieved by Theracurmin did not increase the incidence of adverse events in cancer patients receiving gemcitabine-based chemotherapy

A phase I study investigating the safety and pharmacokinetics of highly bioavailable curcumin (Theracurmin) in cancer patients Kanai M Otsuka Y Otsuka K Sato M Nishimura T Mori Y Kawaguchi M Hatano E Kodama Y Matsumoto S Murakami Y Imaizumi A Chiba T Nishihira J Shibata H Cancer chemotherapy and pharmacology 201371(6)1521-30 httpwwwncbinlmnihgovpubmed23543271 e-mail kanaikuhpkyoto-uacjp

Theracurmin

Pancreatic Cancer - Combination treatment with Gemcitabine and Theracurmin

Phase II Trial with Gemcitabine and Theracurmin Masashi Kanai tested the improved concentrated version Theracurmin in clinical trials Results Three patients safely continued THERACURMINreg treatment for gt 9 mo Fatigue and functioning-associated quality of life (QOL) scores scaled by EORTC QLQ-C30 significantly improved following THERACURMINreg administration Curcumin may irritate the intestine potentially increasing abdominal pain in patients with intestinal obstructions due to peritonitis carcinomatosa or other complications These should be checked for by CT scan prior to commencement future clinical trials should be cautious when administering curcumin to these types of patients ndash CT scan first THERACURMINreg treatment leads to better survival times by delaying EMT and slowing down the rate of tumour growth

Therapeutic applications of curcumin for patients with pancreatic cancer World J Gastroenterol 2014 20(28) 9384-9391 Available from URL httpwwwwjgnetcom1007-9327fullv20i289384htm DOI httpdxdoiorg103748wjgv20i289384 e-mail kanaikuhpkyoto-uacjp

Minnelide (Triptolide)

Pancreatic Cancer - Minnelide (Triptolide)

Minnelide A team at the University of Minnesota developed Minnelide as a soluble version of Triptolide for use in trials Results All the mice treated with Minnelide survived until the end of the trial

Minnelide a novel drug for pancreatic and liver cancer Sulagna Banerjee a Ashok Saluja Pancreatology 15 (2015) S39eS43 httpwwwpancreatologynetarticleS1424-390328152900573-6abstract E-mail address asalujaumnedu (A Saluja)

Minnelide activates two different cell death pathways 1) apoptosis in MIA PaCa-2 Capan-1 BxPC-3 cells and 2) autophagy in S2-013 S2-VP10 and Hs766T cells

Salinomycin

Pancreatic Cancer -

Combination treatment with Salinomycin A team led by Piyush B Gupta published a paper in the Journal ldquoCellrdquo setting out their findings from screening a collection of 16000 compounds httpwwwcellcomcellissuepii=S0092-8674280929X0017-6 They found that Salinomycin an antibiotic used to treat cattle was lethal to human Cancer Stem Cells (CSC) when tested on stem-like HMLER-shEcad cells Further research showed (Guan-Nan Zhang et al 2011) that a combination of gemcitabine and salinomycin eliminates pancreatic cancer cells wwwelseviercomlocatecanlet or httpwwwncbinlmnihgovpubmed22030254 Treatment has moved from in vitro to in vivo with a researcher from Germany whose work wersquoll look at next

Salinomycin

Pancreatic Cancer - Salinomycin ndash How it Works

Salinomycin A Novel Anti-Cancer Agent with Known Anti-Coccidial Activities Shuang Zhou Fengfei Wang Eric T Wong Ekokobe Fonkem Tze-Chen Hsieh Joseph M Wu and Erxi Wu Curr Med Chem 2013 20(33) 4095ndash4101 httpwwwncbinlmnihgovpmcarticlesPMC4102832 Email erxiwundsuedu

Salinomycin

Pancreatic Cancer -

Targeting Human Cancer Stem Cells (CSCs) with Salinomycin A German team has treated patients with Salinomycin killing regular tumour cells highly indolent tumour cells and Cancer Stem Cells (CSCs) Traditional Pancreatic treatment with chemotheraputic drugs such as Gemcitabine isnrsquot successful in knocking down CSCs or in preventing metastases over prolonged periods of time The corresponding author is Cord Naujokat Patients with breast cancer ovarian cancer head cancer neck cancer and cancer of the vulva were all treated where conventional chemo and radiotherapy had failed to kill Cancer Stem Cells (CSCs) All the patients treated had exhausted other treatment options and had advanced metastatic cancers

Salinomycin as a Drug for Targeting Human Cancer Stem Cells Cord Naujokat and Roman Steinhart Journal of Biomedicine and Biotechnology Volume 2012 Article ID 950658 17 pages doi1011552012950658 httpwwwhindawicomjournalsbmri2012950658 Prof Cord Naujokat profnaujokatgmxde or cordnaujokatmeduni-heidelbergde

Salinomycin

Pancreatic Cancer -

Combination Therapy Gemcitabine with Salinomycin A Chinese team has shown that combining Gemcitabine with Salinomycin kills pancreatic cancer cells

Combination of salinomycin and gemcitabine eliminates pancreatic cancer cells Guan-Nan Zhang Yi Liang Ling-Jun Zhou Shu-Peng Chen Ge Chen Tai-Ping Zhang Tiebang Kang Yu-Pei Zhao Cancer Letters 313 (2011) 137-144 doi 1 0101 6jcanlet201105030 httpwwwcancerlettersinfoarticleS0304-383528112900307-7abstract E-mail address zhao8028263net (Y-P Zhao)

Data indicated that SAL can inhibit pancreatic CSCs More importantly their results indicated combined treatment of SAL and GEM eliminated both CSCs and differentiated cells

Salinomycin

Pancreatic Cancer - Salinomycinrsquos Modus Operandi

Combination Therapy Gemcitabine with Salinomycin Salinomycin triggers tumour cell apoptosis Mechanisms involved include mitochondrial amp cellular K+ efflux with loss of K+ interference with mitochondrial function caspase activation by the mitochondrial pathway generation of reactive oxygen species (ROS) endoplasmic reticulum stress autophagy inhibition of Akt activation of p38 kinase and erythrocyte cell membrane scrambling

Triggering of Erythrocyte Cell Membrane Scrambling by Salinomycin Rosi Bissinger Abaid Malik Kashif Jilani and Florian Lang Basic amp Clinical Pharmacology amp Toxicology 2014 115 396ndash402 Doi 101111bcpt12250 httponlinelibrarywileycomdoi101111bcpt12250pdf E-mail florianlanguni-tuebingende

Salinomycin specifically inhibits the Wntβ-catenin signaling pathway initiated by Wnt1

Salinomycin selectively inhibited Wnt signaling mediated by Wnt1Fzd5LRP6

Protein Kinase D1

Pancreatic Cancer - Protein Kinase D1

Gene Therapy for Pancreatic Tumours - Protein Kinase D1 A team from the US Mayo Clinic and the University of Oslo under Dr Peter Storz has identified a molecule that makes normal pancreatic cells change their shape The gene found is known as protein kinase D1 or PKD1 When they blocked PKD1 pancreatic progenitor cell production shown in the production of duct-like cells and lesions decreased The model tells us that PKD1 is essential for the initial transformation from acinar to duct-like cells

Protein kinase D1 drives pancreatic acinar cell reprogramming and progression to intraepithelial neoplasia Geou-Yarh Liou Heike Doumlppler Ursula B Braun Richard Panayiotou Michele Scotti Buzhardt Derek C Radisky Howard C Crawford Alan P Fields Nicole R Murray Q Jane Wang Michael Leitges amp Peter Storz Nature Communications 6 Article number 6200 doi101038ncomms7200 httpwwwnaturecomncomms2015150220ncomms7200pdfncomms7200pdfaccess httpwwwncbinlmnihgovpubmed25698580 Email StorzPetermayoedu

QS molecule O-DDHSL

Pancreatic Cancer - QS molecule O-DDHSL

QS molecule O-DDHSL The combined findings from a study by Ashwath Kumarrsquos group at the Comparative Oncology and Epigenetics Laboratory Veterinary Medicine and Surgery University of Missouri Columbia Missouri demonstrate that QS molecule O-DDHSL decreases cell viability promotes apoptosis by activating caspases and inhibits the wound healing process O-DDHSL modulates genes responsible for migration such as RhoC cofilin and IQGAP-1 However they observed that O-DDHSL also affect some of the normal epithelial cells properties similar to that of tumour cells which could be a limiting factor when it comes to the clinical application of this molecule The potential for O-DDHSL as a possible chemotherapeutic agent for pancreatic cancer needs further in vivo evaluation httpwwwplosoneorgarticlefetchObjectactionuri=infodoi101371journalpone0106480amprepresentation=PDF

QS molecule O-DDHSL

Pancreatic Cancer - QS molecule O-DDHSL

QS molecule O-DDHSL Panc-1 (66103 cells per well) was treated with different concentrations of O-DDHSL for 24 and 48 h Significant decrease in cell viability was observed with 200ndash300 mM O-DDHSL (P005) after 24 h At 48 h cell viability decrease was significant at ODDHSL concentration at or above 100 mM (P002 n = 3) However HPDE cell viability was not affected after 48 h except for a slight decrease at 300 mM O-DDHSL No effect was observed with O-HHSL B ndash Aspc-1 (66103 cells per well) was more sensitive to O-DDHSL exposure than Panc-1 A significant decrease (P002) was observed in viability $25 mM O-DDHSL after 24 or 48 h (n = 3) Cell viability was not affected by O-HHSL In both cases DMSO (002) was used as diluent control which did not affect the cell viability per se

Bacterial Quorum Sensing Molecule N-3-Oxo-Dodecanoyl-L-Homoserine Lactone Causes Direct Cytotoxicity and Reduced Cell Motility in Human Pancreatic Carcinoma Cells Ashwath S Kumar Jeffrey N Bryan Senthil R Kumar doi101371journalpone0106480 httpwwwplosoneorgarticlefetchObjectactionuri=infodoi101371journalpone0106480amprepresentation=PDF Email kumarsmissouriedu

QS molecule O-DDHSL

Pancreatic Cancer - QS molecule O-DDHSL

QS molecule O-DDHSL Panc-1 cells were plated on a layer of matrigel in chamber slides in serum free DMEMF12 media and allowed to grow for two weeks O-DDHSL (200 mM) was added to the cells and incubated for 48 h at 37uC Subsequently a fluorescent dye Calcein AM was added and further incubated for 2 h for its uptake by the cells CndashE ndashLight

Bacterial Quorum Sensing Molecule N-3-Oxo-Dodecanoyl-L-Homoserine Lactone Causes Direct Cytotoxicity and Reduced Cell Motility in Human Pancreatic Carcinoma Cells Ashwath S Kumar Jeffrey N Bryan Senthil R Kumar doi101371journalpone0106480 httpwwwplosoneorgarticlefetchObjectactionuri=infodoi101371journalpone0106480amprepresentation=PDF Email kumarsmissouriedu

microsopy pictures of cells growing on matrigel before and after addition of O-DDHSL showing morphological changes of apoptosis (toppanel) Bottom panel shows the uptake of Calcein AM dye in the cells before and after treatment with O-DDHSL showing dye uptake by viable cellsand loss of cell viability resulting in the absence of dye uptake (406)

interleukin-10 (IL-10) gene

Pancreatic Cancer -

Viro Therapy cw Immunotherapy for Pancreatic Tumours The QMUL team at Barts Cancer Institute armed the Vaccinia virus with a copy of the interleukin-10 (IL-10) gene which would express proteins in the cancer cell once infected by the Vaccinia Researchers hoped that this would allow the virus to take hold and persist for longer ldquoMany viruses use IL-10 to hide from the hostrsquos immune system so we thought wersquod use this natural strategy to investigate whether it would improve Vacciniarsquos effectivenessrdquo said Dr Yaohe Wang who led the research The results suggest that VVL∆TK-IL10 has strong potential as an antitumor therapeutic for Pancreatic Cancer

A Vaccinia virus armed with interleukin-10 is a promising therapeutic agent for treatment of murine pancreatic cancer Louisa Chard1 Eleni Maniati2 Pengju Wang3 Zhongxian Zhang3 Dongling Gao3 Jiwei Wang3 Fengyu Cao4 Jahangir Ahmed1 Margueritte EI Khouri1 Jonathan Hughes1 Shengdian Wang5 Xiaozhu Li6 Bela Denes7 Istvan Fodor8 Thorsten Hagemann9 Nicholas R Lemoine10 and Yaohe Wang1 doi 1011581078-0432CCR-14-0464 httpclincancerresaacrjournalsorgcontentearly201411211078-0432CCR-14-0464abstract Email yaohewangqmulacuk

A transmission electron micrograph of Vaccinia (via CDC Public Health Image Library)

New delivery method ndash Polymeric Micelles of Salinomycin

Pancreatic Cancer -

Targeting Pancreatic Cancer with Polymeric Micelles of Salinomycin An Iranian team developed a technique to deliver Salinomycin in a better targeted way using Polymeric Micelles In gemcitabine-resistant AsPC-1 cells SAL was found to significantly increase cell mortality and apoptosis It was also observed that SAL micellar formulations inhibited invasion and harnessed EMT in spite of induced expression of Snail The in vivo anti-tumour experiment showed significant tumour eradication and the highest survival probability in mice treated with SAL PMs As with Minnelide 100 of the mice survived

Polymeric Micelles of PEG-PLA Copolymer as a Carrier for Salinomycin Against Gemcitabine-Resistant Pancreatic Cancer Zahra Daman Hamed Montazeri Masoumeh Azizi Faegheh Rezaie Seyed Nasser Ostad Mohsen Amini Kambiz GilaniPharm Res (2015) 323756ndash3767 DOI 101007s11095-015-1737-8 httplinkspringercomarticle1010072Fs11095-015-1737-8 Email Kambiz Gilani gilanitumsacir

Summary

Pancreatic Cancer -

Present research on the Hippo pathway is summarised on the slide below

Hippo signaling pathway in liver and pancreas the potential drug target for tumor therapy Delin Konga Yicheng Zhaoa Tong Mena amp Chun-Bo Tenga

Journal of Drug Targeting Volume 23 Issue 2 2015 httpwwwtandfonlinecomdoiabs1031091061186X2014983522 E-mail chunbotengnefueducn