GENETICS

It's all in the genes

Dr. Amit Verma, MD

In-charge, Personalised Cancer Medicine Clinic;
Consultant, Molecular Oncology and Cancer Genetics Max Cancer Centre, New Delhi

February 03, 2016

Treating two people with the same type of cancer in the same way is not a wise move to achieve the best results

Human cancers arise via a multistep mutagenic process reflective of genetic and epigenetic changes driving normal cells into a highly malignant state. Many human tumour types with distinct genotypes have essential alterations in cell physiology that appear to collectively dictate the malignant phenotype. These cellular processes are self-sufficient in growth signals, insensitive to growth-inhibitory signals, evade programmed cell death, have limitless replication potential, sustained angiogenesis, evade immune surveillance and invasion/metastasis. With such a complex interplay of various mechanisms, no two cancers are alike, just as no two people are alike. In addition, every person’s cancer and personal response to treatment is unique. So, treating two people with the same type of cancer in the same way is not a wise move to achieve the best results. Recent technological advances have made it possible to generate a profile of the abnormalities in the genetic code of a tumour and the patient.

Precision Cancer Medicine (PCM) is a multi-faceted, integrated approach to patient care that requires treating the patient based on the unique genetic alterations, thus offering the right treatment for the right patient. Novel therapeutic approaches are being developed to overcome the effect of the genetic alterations (gene mutations) and activate the immune system. These approaches include Targeted Therapy, Immunotherapy, Gene Therapy, among others. Using the genetic information, doctors hope to identify treatment strategies that may be more effective with fewer side-effects.

Targeted Therapy

Small differences between normal cells and cancer cells are called Cellular Targets and special type of chemotherapy developed to attack a certain target on cancer cells is called Targeted Therapy. Targeted drugs are mainly of two types—Monoclonal antibody and Small-molecule inhibitors. Monoclonal antibody drugs, also called Biologics, are man-made versions of large immune system proteins (called antibodies) and Small-molecule inhibitors are chemicals, like most other types of drugs. Targeted drugs can be grouped by how they work or what part of a cell they target, like Signal transduction inhibitors, Angiogenesis inhibitors, Apoptosis-inducing drugs, Immunotherapy drugs, Monoclonal antibodies attached to toxins, among others. Few examples of targeted therapies are Trastuzumab, Pertuzumab, Lapatinib for Breast Cancer, Bevacizumab and Cetuximab for Colon Cancer, Gefitinib and Erlotinib for Lung Cancer, Sorafenib for Liver cancer, Imatinib for GIST and Chronic Myeloid Leukemia.

Immunotherapy

It involves activating one’s own immune system against the cancer cells. Most cancer vaccines work the same way like normal vaccine given during childhood. Immunotherapies either stimulate the activities of specific components of the immune system or counteract signals produced by cancer cells that suppress immune responses. The goal is to help treat cancer or to help keep it from coming back after other treatments. Immunotherapies are of two types—Cancer Therapeutic Vaccine and Immune Check Point Modulators.

Cancer Therapeutic Vaccine

The cancer vaccines are made up of cancer cells, parts of cells, or pure antigens or antigen-presenting cells (Dendritic Cells) activating the immune system to attack cancer cells with one or more specific antigens. Because the immune system has special cells for memory, it’s hoped that the vaccine might continue to work long. Spilucel-T is Dendritic Vaccine for metastatic prostate cancer, which is approved by Food and Drug Administration (FDA).

Immune Check Point Modulators

One immunotherapy approach is to block the ability of certain proteins, called immune checkpoint proteins, to limit the strength and duration of immune responses. These proteins normally keep immune responses in check by preventing overly intense responses that might damage normal cells as well as abnormal cells. But tumours can commandeer these proteins and use them to evade immune responses. Blocking the activity of immune checkpoint proteins releases the inhibition thus activating the immune system resulting in increased ability to destroy cancer cells. Ipilimumab, which blocks the activity of a checkpoint protein known as CTLA4, is an immune checkpoint inhibitors that is approved by FDA for the treatment of advanced melanoma. CTLA4 is expressed on the surface of activated immune cells called cytotoxic T lymphocytes and acts as a "switch" to inactivate these T cells; Ipilimumab binds to CTLA4 and prevents it from sending its inhibitory signal. Checkpoint inhibitors Nivolumab and Pembrolizumab, work in a similar way, but they target a different checkpoint protein on activated T cells known as PD-1. Nivolumab is approved to treat Melanoma or Lung cancer, and Pembrolizumab is approved to treat Melanoma.

Gene Therapy

Inserting genetic material into cancer cells to give them a new function or restore a missing function is called Gene Therapy, which is designed to modify cancer cells at the molecular level and correct the faulty gene with a healthy one. A vector is required to deliver the gene to the target cell and commonly used vectors are an inactive virus or liposome, a tiny fat bubble. Although gene therapy available through clinical trials may be one way to overcome these changes and treat or prevent cancer. Few examples of Gene Therapy are ONYX-15 is adenovirus inserting the functional P53 gene and inducing cell death (apoptosis), VEGF-siRNA for inhibiting tumor angiogenesis (Anti-angiogenesis), TG2-siRNA for overcoming drug resistance and metastasis, EpH2-siRNA for inhibiting survival signalling, among others.