Molecular Targeted Therapies

Dr Ankur shah

The Role of Systemic Therapy

• Treatment of the whole body• Intent?

– Induction therapy– Adjuvant therapy– Palliative

Chemotherapy vs Targeted Therapy

• Chemotherapy:– Drugs that effect cells that are doubling– Not very specific– Mostly intravenous, some oral agents– Cytotoxic

• Targeted therapy:– Drugs that inhibit a more specific target in cells– Many are oral agents– Mixture of cytostatic and cytotoxic

Six Essential Alterationsin Cell Physiology in Malignancy

Limitless replicativepotential

Tissue invasion& metastasis

Sustainedangiogenesis

Insensitivity toanti-growth signals

Self-sufficiency ingrowth signals

Evadingapoptosis

Targets for classical drugs?

Targets for novel drugs?

Hanahan & Weinberg,Cell 100:57 (2000)

What is Targeted Therapy?

A “smart” bomb versus a “cluster” bomb.Dr. Nevin Murray

Targeted Therapy: A definition• Drugs targeted at pathways, processes and physiology which are uniquely

disrupted in cancer cells:– Receptors– Genes– Angiogenesis– Tumor pH

• Examples:– tyrosine kinase pathway (bcr-abl, PDGF)– proteosomal pathways– survival signals (MCL1, BCL2)– heat shock proteins– immunological activation/tolerance

Attempts to take advantage of a genetic change in the malignant cells

The revolution of molecular targeted cancer therapy.

and the journey still continues…Yarden Y The Oncologist 2011;16:23-29

Signaling complexity: The engineering perspective.

Yarden Y The Oncologist 2011;16:23-29

©2011 by AlphaMed Press

How to hit the target

• If you know the target, and there is only one target you can be very specific.

• If you don’t really know or it’s a really big target, a larger weapon may be needed.

But all is not lost…

• Return to the fundamental assumption.• Targeted therapy works when you can identify

and validate the target.– Need to enrich the population for the target:

Herceptin– May need to hit more than one target

Leveraging your opponents weight, or how targeted therapy can work with other treatments and toss the opponent out of the ring

The Origins of CML

Imatinib

BRAF Mutation in Melanoma

EML4-ALK Mutation in Lung Cancer

• Present in 3-5% of non-small cell lung cancer, usually adenocarcinoma

• Mutation leads to formation of a fusion gene that codes for an abnormal tyrosine kinase receptor

Response to crizotinib in patients with EML-ALK NSCLCA

Drugs in the Pipeline for ALK

Her-2/neu

• About 25% of breast cancer cases are associated with a amplification of the genes coding for a cell surface receptor called Her-2/neu

• These cells may a 1000 fold increase in the number of these receptors over normal breast cells

• Associated with rapid growth

Herceptin

There Are Multiple Agents Already Available

Non-Hodgkin Lymphoma

Old News Targeted Therapy

(But crucial in breast cancer)

Normal Estrogen Effects in Breast Cells

Anti-estrogen Therapy in Breast Cancer

Antibody-Drug Conjugates

A New Agent in Hodgkin's Disease

Stimulating an Immune Response

New Agent in Melanoma Therapy

Pushing Immune Cells to Recognize Cancer Cells

Sipuleucel-T in Prostate Cancer

CONCLUSIONS

• Targeted therapy can exploit fragile aspects of oncogenic networks

• Drug resistance reflects system plasticity, and may be overcome by drug combinations.

• System controls, such as receptor endocytosis and transcriptional feedback loops, are often defective in cancer, and may be another source of exploitations with future therapies.

Targeted Therapy: The Future• Modern biology has identified a host of new potential

targets for cancer therapy

• Drugs interacting with these targets are available.

• The benefit of these agents is dependent upon the criticality of the target. More than one target may need to be inhibited.

• New agents may “tip the balance” when combined with chemotherapy, radiation.