cancer therapy - milestones

8/14/2019 Cancer Therapy - Milestones

1/24

Cancer Therapy:Successes and failures


2/24

Key Issues

Chemotherapy drug development over the last 40 years Combination Chemotherapy

Adjuvant chemotherapy

Drug screening programmes

The platinum drugs

Hormonal therapy tamoxifen story

Targeted therapy immunotherapy

Multiple drug resistance (MDR)

Epidemiology


3/24


4/24

CombinationChemotherapy

Extended to the lymphomas in 1963 Vincent DeVita George Canellos, NCI, in the

late 1960s.

Nitrogen mustard, vincristine, procarbazine andprednisone: MOPP regimen.

could cure patients with Hodgkin's and non-Hodgkin's lymphoma.

Nearly all successful cancer chemotherapyregimens use the model of multiple drugs givensimultaneously.


5/24

Adjuvant therapy

Animal studies demonstrated that chemotherapywas more effective when used to treat tumours ofsmaller size.

Reduce tumour burden by surgery them treatremainder with chemo.

Emil Frei used high dose methotrexate to preventedrecurrence of osteosarcoma following surgicalremoval of the primary tumour.

5-fluorouracil was later shown to improve survivalwhen used as an adjuvant to in colon cancer.

adjuvant chemotherapy after complete surgicalresection of breast tumours significantly extendedsurvival for advanced cancer.


6/24

NCI Drug ScreeningProgramme

1956: Gordon Zubrod, led the development of antimalarial agents for the

United States Army took over the Division ofCancer Treatment of the NCI.

Guided development of new drugs.

Two decades that followed, NCCSC established totest anticancer agents.

Zubrod interested in natural products ofplant and marine sources, a controversialprogramme.

Led to the discovery of Taxanes (in 1964) Camptothecins (in 1966).


7/24

The Platinum Drugs

Platinum-based agents

Cisplatin discovered at Michigan State University by BarnettRosenberg working under an NCI contract.

A serendipitous discovery: Rosenberg wanted to explore theeffects of an electric field on the growth of bacteria.

Bacteria ceased to divide in an electric field. T

The inhibition of bacterial division was pinpointed to anelectrolysis product of the platinum electrode.

Initiated studies into the effects of platinum compounds on cellCisplatin synthesised.

Pivotal in the cure of advanced testicular cancer. Subsequently,

Eve Wiltshaw: Institute of Cancer Research UK developedcarboplatin with broad antitumour activity and lessnephrotoxicity.


8/24

Some of the players

1. Emil Frei

2. Geoffrey Holland3. Vincent DeVita

4. Gordon Zubrod


9/24

Breast Cancer: Tamoxifen

Tamoxifen: estrogen receptormodulator for breast cancer. early and advanced breast cancer in

pre - and post-menopausal women World's largest selling breastcancer treatment.

Used as prophylaxis: For women at high risk.

Reduction of contralateral (in theopposite breast) breast cancer.


10/24

Tamoxifen

Tamoxifen Estradiol


11/24

Tamoxifen

Tamoxifen: invented by AstraZeneca brand names Nolvadex, Istubal, Valodex.

Tamoxifen is taken for up to 5yrs or for life in

advanced disease.

Improved survival rates by 40-50%.

Usually given in combination with traditionalchemotherapy (methotrexate, 5FU)


12/24

Immunotherapy

Traditionally cancer treated with:

Surgery, radiotherapy, chemotherapy(individually or in combination).

Chemo and radiotherapy affect healthytissue.

Toxic side effects and development of drug

and radio-resistance

Immunotherapy may avoid problems oftoxicity and resistance


13/24

mAB Tradename

Tumour Company Date

Rituximab Rituxan Non-Hodgkin'slymphoma

Roche/Genentech 1997

Trastuzumab Herceptin Breast CA Genentech 1998

Gemtizumab Mylotag AML Wyeth/Celltech 2000

Alemtuzumab Campath CLL Genzyme 2001Ibritumomab Zevalin Non-Hodgkin's

lymphoma

Biogen Idec 2002

Tositumomab Bexxar Non-Hodgkin's

lymphoma

GSK/Corixar 2003

Cetuximab Erbitux Colorectal Imclone/BMS 2004

Bevacizumab Avastin Colorectal Genentech 2004


14/24

Immunotherapy

Development of mAB therapy dependent ona greater understanding of signaltransduction pathways.

mABs competitively bind to cell surfacereceptor and lead to receptor destruction.

No side effects or toxicity.

Early days


15/24

Resistance to chemotherapy

Conventional cancer chemotherapy is limited by tumourcells which exhibit multidrug resistance (MDR).

MDR is defined as resistance of tumour cells to thecytostatic or cytotoxic actions of: Multiple

Structurally dissimilar

Functionally divergent, drugs commonly used in cancerchemotherapy.

MDR can be:

Intrinsic: The tumour is non-responsive (refractory) at the startof treatment

Acquired when the tumour initially responds but then relapsesand becomes refractory to treatment


16/24

What causes MDR?

Transporter molecules (usually membrane bound) are

mediators of MDR.

P-glycoprotein (P-gp) is a prototypical MDR protein

Identified as a 170kDa glycoprotein abundantly expressed

in MDR cells.

Cloning and purification of MDR gene demonstrated that itis a unidirectional ATP-dependent drug efflux pump.

A product of the MDR1 gene

ATP binding cassette superfamily (small molecule ion

transporters


17/24

Epidemiology

A success indicating a huge failure: Understanding the causes of cancer has been a

major advance

Studies into the Causes

Risks

Incidence

Mortality

Indicate that the problem of cancer hashardly been addresses in a satisfactory way


18/24

A Global Concern

1990 2000 2010

60 million deaths 80 million deaths

2/3 in developing countries

With 5% of the resources to deal with the

problem

40 million of these deaths are preventable


19/24

A Global Concern

9 Million new diagnoses each year

5 million deaths each year

10% of all deaths in the world each year

Usually regarded as a problem of developedcountries

More than half of of all cancers are seen in ofthe worlds population who live in developingcountries


20/24

Epidemiology of Cancer

Studies on the epidemiology of cancer break

down into two basic areas.

The biology/molecular genetics of cancer.

The sociology of cancer.

Understanding both of these areas in critical forcancer control.


21/24

Sociology of Cancer

Where people live.

Geographic and temporal variability

Habits Smoking ----- Lung cancer.

Diet ------------ Stomach and colon cancer.

Food preservatives --------- Stomach and liver cancer.

Environmental hazards Viruses and liver cancer.


22/24

Cancer Incidence


23/24

CRU

K

Statist i

cs

2000

Sur

vival


24/24

Logical but major advances Combination Chemotherapy

Adjuvant chemotherapy

Drug screening programmes

The platinum drugs

Hormonal therapy tamoxifen story

Targeted therapy immunotherapy

Multiple drug resistance (MDR)

Epidemiology

Summary

cancer therapy - milestones

Documents