Cancer Therapy - Milestones

Cancer Therapy: Successes and failures

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

Combination Chemotherapy • 1965: a most important break-through in cancer therapy occurred. – James Holland, Emil Freireich, Emil Frei • Proposed the idea of combination chemotherapy using drugs with different mechanisms of action. • cancer cells might develop resistant to the a single agent, but unlikely to become resistant to multiple. • Administered methotrexate vincristine, 6mercaptopurine and prednisone: POMP regimen – Acute lyphocytic leukaemia – children – ALL now largely curable even at advanced stages

Combination Chemotherapy • Extended to the lymphomas in 1963 – Vincent DeVita George Canellos, NCI, in the late 1960s. • Nitrogen mustard, vincristine, procarbazine and prednisone: MOPP regimen. • could cure patients with Hodgkin's and nonHodgkin's lymphoma. • Nearly all successful cancer chemotherapy regimens use the model of multiple drugs given simultaneously.

Adjuvant therapy • Animal studies demonstrated that chemotherapy was more effective when used to treat tumours of smaller size. – Reduce tumour burden by surgery them treat remainder with chemo. • Emil Frei used high dose methotrexate to prevented recurrence of osteosarcoma following surgical removal of the primary tumour. • 5-fluorouracil was later shown to improve survival when used as an adjuvant to in colon cancer. •

adjuvant chemotherapy after complete surgical resection of breast tumours significantly extended survival for advanced cancer.

NCI Drug Screening Programme • 1956: Gordon Zubrod, – led the development of antimalarial agents for the United States Army took over the Division of Cancer Treatment of the NCI. – Guided development of new drugs. – Two decades that followed, NCCSC established to test anticancer agents.

• Zubrod interested in natural products of plant and marine sources, a controversial programme. • Led to the discovery of – Taxanes (in 1964) – Camptothecins (in 1966).

The Platinum Drugs • •

Platinum-based agents Cisplatin discovered at Michigan State University by Barnett Rosenberg working under an NCI contract.

•

A serendipitous discovery: Rosenberg wanted to explore the effects 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 an electrolysis product of the platinum electrode.

•

Initiated studies into the effects of platinum compounds on cell Cisplatin synthesised.

•

Pivotal in the cure of advanced testicular cancer. Subsequently,

•

Eve Wiltshaw: Institute of Cancer Research UK developed carboplatin with broad antitumour activity and less nephrotoxicity.

Some of the players

1. 2. 3. 4.

Emil Frei Geoffrey Holland Vincent DeVita Gordon Zubrod

Breast Cancer: Tamoxifen • Tamoxifen: estrogen receptor modulator for breast cancer. – early and advanced breast cancer in pre - and post-menopausal women

• World's largest selling breast cancer treatment. • Used as prophylaxis: – For women at high risk. – Reduction of contralateral (in the opposite breast) breast cancer.

Tamoxifen

Tamoxifen

Estradiol

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 traditional chemotherapy (methotrexate, 5FU)

Immunotherapy • Traditionally cancer treated with: – Surgery, radiotherapy, chemotherapy (individually or in combination). • Chemo and radiotherapy affect healthy tissue. • Toxic side effects and development of drug and radio-resistance • Immunotherapy may avoid problems of toxicity and resistance

mAB

Trade name

Tumour

Company

Date

Rituximab

Rituxan

Non-Hodgkin's lymphoma

Roche/Genentec 1997 h

Trastuzumab

Herceptin Breast CA

Genentech

1998

Gemtizumab

Mylotag

AML

Wyeth/Celltech

2000

Alemtuzumab

Campath

CLL

Genzyme

2001

Ibritumomab

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

Immunotherapy • Development of mAB therapy dependent on a greater understanding of signal transduction pathways. • mABs competitively bind to cell surface receptor and lead to receptor destruction. • No side effects or toxicity. • Early days

Resistance to chemotherapy • Conventional cancer chemotherapy is limited by tumour cells which exhibit multidrug resistance (MDR). • MDR is defined as resistance of tumour cells to the cytostatic or cytotoxic actions of: – Multiple – Structurally dissimilar – Functionally divergent, drugs commonly used in cancer chemotherapy.

• MDR can be: – Intrinsic: The tumour is non-responsive (refractory) at the start of treatment – Acquired when the tumour initially responds but then relapses and becomes refractory to treatment

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 it is a unidirectional ATP-dependent drug efflux pump. – A product of the MDR1 gene – ATP binding cassette superfamily (small molecule ion transporters

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 has hardly been addresses in a satisfactory way

A Global Concern • 1990 60 million deaths

2000

2010

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

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 developed countries • More than half of of all cancers are seen in ¾ of the world’s population who live in developing countries

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 for cancer control.

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.

Cancer Incidence

CRUK Statistics 2000 Survival

Summary • 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