personalized medicine in oncology

Personalized Medicine in Oncology: The Future Is Now

Bita Fakhri

04/07/2015

First Efforts (1940-1952)

• German introduction of chemical warfare during WWII

• A German air raid in Bari, Italy led to the exposure of more than one thousand people to the John Harvey’s secret cargo composed of mustard gas bombs.

• Autopsies of the victims suggested profound lymphoid and myeloid suppression

First Efforts (1940-1952)

• Set up an animal model - they established lymphomas in mice

• Demonstrated they could treat them with mustard agents.

• In collaboration with a thoracic surgeon, Gustaf Lindskog, they injected nitrogen mustard into a patient with NHL.

• They observed a dramatic reduction in the patient's tumor masses. Although this effect lasted only a few weeks, and the patient had to return for another set of treatment, this was the first step to the realization that cancer could be treated by pharmacological agents

Gustaf Lindskog

Antifolates (1948)

• Studied the effects of folic acid on leukemia patients.

• Folic acid, a vitamin crucial for DNA metabolism, had been discovered by Lucy Wills, when she was working in India, in 1937.

• Folate seemed to stimulate the proliferation of ALL cells when administered to children with this cancer.

• Farber used folate analogues. These analogues — first aminopterin and then amethopterin (now methotrexate) were antagonistic to folic acid, and blocked the function of folate-requiring enzymes.

Sydney Farber – the father of modern chemotherapy

National Treatment Effort by the US (1955)

• 1955: The US congress created a National Cancer Chemotherapy Service Center (NCCSC) at the NCI in response to early successes. This was the first federal program to promote drug discovery for cancer.

• 6-MP, Vinca alkaloids

First Solid Tumor To Be Treated with Chemotherpy (1958)

• When choriocarcinoma patients were being treated with methotrexate, urine levels of the hormone hCG dropped steadily.

• Li hypothesized that the patients' tumors were secreting hCG, and as a result, that the level of hCG in a patient's urine could be used to measure the effectiveness of a particular treatment.

• He concluded that a dose of 100–125 mg given every day for four or five days was more effective than a single, larger dose

• The NCI disapproved, feeling that by continuing treatment Li was experimenting on his patients and unnecessarily poisoning them with the chemotherapy drug. In 1957, the NCI fired Li and he returned to Sloan-Kettering.

Roy Hertz – Min Chiu Li

Combination Chemotherapy (1965)

• Hypothesized cancer chemotherapy should follow the strategy of antibiotic therapy for tuberculosis with combinations of drugs, each with a different mechanism of action. Cancer cells could mutate to become resistant to a single agent, but by using different drugs concurrently it would be more difficult for the tumor to develop resistance to the combination.

Combination Chemotherapy (1965)

• POMP regimen — and induced long-term remissions in children with ALL.

• This approach was extended to the lymphomas by Vincent DeVita and George Canellos at the NCI. In the late 1960s MOPP regimen— could cure patients with HL and NHL.

• Currently, nearly all successful cancer chemotherapy regimens use this paradigm of multiple drugs given simultaneously, called combination chemotherapy or polychemotherapy.

Dr. Vincent DeVita

Adjuvent Chemotherapy (1972-75)

• If the tumor burden could be reduced first by surgery, then chemotherapy may be able to clear away any remaining malignant cells. –"adjuvant therapy“

• Emil Frei — high doses of methotrexate prevented recurrence of osteosarcoma following surgical removal of the primary tumor.

• Emil Frie – 5-FU, an inhibitor of DNA synthesis, was later shown to improve survival when used as an adjuvant to surgery in treating patients with colon cancer.

Adjuvant Chemotherapy (1972-75)

• The landmark trial of Bernard Fisher, chair of the National Surgical Adjuvant Breast and Bowel Project, proved adjuvant therapy after complete surgical resection of breast tumors significantly extended survival — particularly in more advanced cancer.

Richard Nixon signs the National Cancer Act of 1971

Richard Nixon signs the National Cancer Act of 1971

• Create new cancer centers and manpower training programs

• Appoint advisory committees, allowing the director to explore new issues/opportunities.

• Expand the physical location at NIH and other research facilities across the country.

• Award contracts for research

• Collaborate with other federal, state, or local public agencies and private industry

• Conduct cancer control activities

• Establish an international cancer research data bank that collects, catalogues, stores, and disseminates results of cancer research

• Award research grants

New Drugs (1971-current)

Taxanes• Paclitaxel (Taxol) - novel antimitotic agent: promoted microtubule assembly.

• obtained from the bark of the Pacific Yew Tree

• forced the NCI into the costly business of harvesting substantial quantities of yew trees from public lands.

• effective in ovarian cancer therapy.

Camptothecins

• derived from a Chinese ornamental tree

• inhibits topoisomerase I, an enzyme that allows DNA unwinding.

• the agent had little antitumor activity in early clinical trials

• dosing was limited by kidney toxicity.

• In 1996 a more stable analogue, irinotecan, won FDA approval for the treatment of colon cancer. Later, this agent would also be used to treat lung and ovarian cancers.

New Drugs

The Pacific Yew - Original Source of Taxol

Camptotheca, Happy Tree, Cancer Tree, Tree Of Life

New Drugs (1971-current)

Platinum-based agents

• Cisplatin, was discovered by a Michigan State University researcher, Barnett Rosenberg, working under an NCI contract.

• Testicular cancer

• United Kingdom extended the clinical usefulness of the platinum compounds with their development of Carboplatin, a cisplatin derivative with broad antitumor activity and comparatively less nephrotoxicity.

Nitrosoureas

• A second group with an NCI contract, led by John Montgomery at the Southern Research Institute

• synthesized nitrosureas, an alkylating agent which cross-links DNA.

• Fludarabine phosphate, a purine analogue which has become a mainstay in treatment of patients with CLL, was another similar development by Montgomery.

Anthracyclines and epipodophyllotoxins

• both of which inhibited the action of topoisomerase II, an enzyme crucial for DNA synthesis.

The Birth of Targeted Therapies (1990s)

Brian Druker - Gleevec

Dennis Slamon - Herceptin


• Trastuzumab is a mAb that interferes with the HER2/neu Receptor.

• The HER proteins stimulate cell proliferation.

• In some cancers, notably certain types of breast cancer, HER2 is over-expressed, and causes cancer cells to reproduce uncontrollably

Denis Slamon


• For 12 years, Dr. Slamon and his colleagues conducted the laboratory and clinical research that led to the development of the new breast cancer drug Herceptin, which targets a specific genetic alteration found in about 25 percent of breast cancer patients.

• improved overall survival in late-stage (metastatic) breast cancer from 20.3 to 25.1 months.

• In early stage breast cancer, reduces the risk of cancer returning after surgery by an absolute risk of 9.5%

• Reduces the risk of death by an absolute risk of 3%

• however increases serious heart problems by an absolute risk of 2.1% which may resolve if treatment is stopped.


• The biotech company Genentech developed trastuzumab jointly with UCLA and gained FDA approval in September 1998.


Janet Rowley, the first geneticist who identified translocation between chromosomes:• 9,22 (1970)

Philadelphia chromosome

• 8,21 AML• 15, 17 APML


• Collaboration between Novartis and Brian Druker at OHSU.

• The first clinical trial of Gleevectook place in 1998 and the drug received FDA approval in May 2001.

Dr. Brian Druker

Targeted Therapies

• Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer.

• Targeted cancer therapies are sometimes called "molecularly targeted drugs," "molecularly targeted therapies," "precision medicines," or similar names.

The Differences between Targeted Therapies and Standard Chemotherapy

Targeted Therapies Standard Chemotherapy

act on specific molecular targets that are associated with cancer

act on all rapidly dividing normal and cancerous cells

deliberately chosen or designed to interact with their target

many standard chemotherapies were identified because they kill cells

cytostatic (that is, they block tumor cell proliferation) cytotoxic (that is, they kill tumor cells)

How Are Targets for Targeted Therapies Identified?

Compare the amount of individual proteins in cancer cells vs. normal cells

• Especially if they are known to be involved in cell growth and survival

• Her2/neu receptor

Determine whether cancer cells produce mutant proteins that drive cancer progression

• BRAF BRAF V600E in many melanomas

• Vemurafenib

Abnormalities in chromosomes that are present in cancer cells but not normal cells

• Fusion proteins drive cancer development

• Imatinib

Forms of Targeted Therapies

Monoclonal antibody drugs

• Man-made versions of large immune system proteins (called antibodies)

• Designed to attack a very specific target on cancer cells

• Referred to as biologics (made in living cells)

• The generic names for these drugs (as opposed to the brand names) all end in -mab; for example, rituximab, panitumumab, etc.

Small-molecule drugs

• chemicals like most other types of drugs

• The generic names for most of these drugs end in -ib; for example, imatinib, dasatinib, etc.

Types of Targeted Therapies

• Signal transduction inhibitors

• Angiogenesis inhibitors

• Apoptosis-inducing drugs

• Immunotherapy drugs

• Monoclonal antibody attached to toxin

Signal Transduction Inhibitors

• The cells in our bodies normally grow (or stop growing) in response to chemical signals they pick up from the area around them.

• These signals are transmitted through proteins to the cell’s control center, telling it what to do.

• In cancer cells, these signals sometimes get stuck in the “on” position, telling the cell to grow even without it getting an outside signal.

Signal Transduction Inhibitors

• EGFR inhibitors, such as cetuximab (Erbitux) and erlotinib (Tarceva), which are used to treat some lung, colorectal, and other cancers.

• HER2 inhibitors, such as trastuzumab (Herceptin) and pertuzumab (Perjeta), which are used to treat some breast, stomach, and other cancers.

• BCR-ABL inhibitors, such as imatinib (Gleevec) and dasatinib (Sprycel), which are used to treat CML.

• BRAF inhibitors, such as vemurafenib (Zelboraf) and dabrafenib (Tafinlar), which are used to treat some melanomas.

Angiogenesis Inhibitors

• Angiogenesis can help tumors grow by giving them their own blood supply.

• Angiogenesis inhibitors stop tumors from making new blood vessels, which greatly limits how big they can grow.

• Many of these drugs work by blocking vascular endothelial growth factor (VEGF) proteins or the VEGF receptors.

• bevacizumab (Avastin) [GBM, NSCLC) and sorafenib, sunitinib

Apoptosis-inducing Drugs

• change the proteins within the cancer cells that cause the cells to die

• bortezomib (Velcade) and carfilzomib (Kyprolis)

Limitations of Targeted Therapies

Resistance

• the target itself changes through mutation

• the tumor finds a new pathway to achieve tumor growth that does not depend on the target.

Solution

• Combination of targeted therapies (melanoma: dabrafenib + trametinib)

• Combination of targeted therapies with traditional chemotherapy (docetaxel + trastuzumab)

Limitations of Targeted Therapies

• some identified targets are difficult to develop because of the target’s structure and/or the way its function is regulated in the cell.

• One example is Ras, a signaling protein that is mutated in as many as one-quarter of all cancers (and in the majority of certain cancer types, such as pancreatic cancer).

Conclusions

• Targeted therapy using mAbs or specific inhibitors of selected events of cancer growth and progression has significantly expanded the molecular treatment of malignancies.

• Moderate adverse effects

• The heterogeneity of the biologic processes underlying cancer

• The right selection of patients

Horizons

• Immune therapy

• Gene therapy

Cancer Patients

• “But the story of leukemia--the story of cancer--isn't the story of doctors who struggle and survive, moving from institution to another. It is the story of patients who struggle and survive, moving from one embankment of illness to another. Resilience, inventiveness, and survivorship--qualities often ascribed to great physicians--are reflected qualities, emanating first from those who struggle with illness and only then mirrored by those who treat them. If the history of medicine is told through the stories of doctors, it is because their contributions stand in place of the more substantive heroism of their patients.”

Salute

Adam's sons are body limbs, to say;

For they're created of the same clay.

Should one organ be troubled by pain,

Others would suffer severe strain.

Thou, careless of people's suffering,

Deserve not the name, "human being".

personalized medicine in oncology

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