Targeting The Invincible – Bull’s Eye

Understandably, cancer cell is different from a normal cell in many ways, and such differences are unique to them. Therefore, if we develop drug against any or many such differences, that drug is likely to have very less collateral damage and provide us with desired maximum “kill rate”. Such a drug is called a targeted drug. With advent of targeted drug therapy, cancer treatment has seen a paradigm shift especially in the last decade so much so that targeted therapy is becoming a part of therapy in almost all cancers.

While targeted drug therapy aims at hitting the destined target and decreasing the side effects by sparing the normal tissues; exactly in the manner a smart or laser bomb does its work in contrast to a cluster bomb; it may not do its work still due to inherent and complex biology of the tumor. We have long known that one size does not fit all, and time has come to provide a tailor made treatment to our patients. Simply put, a therapy which best suits “their” tumor type and biology which may be unique to them. This steps up to the next question – who is the one in whom they will work the best? We have now been able to understand a few of the reasons for individual patient variations and discrepancies in response rates. I will quote a few examples of both targeted therapies and the specific tumor characteristics/biomarkers which defines the exquisite sensitivity to the targeted agent, for your better understanding. I will take the example of lung cancer one the most common and dreaded cancer which almost always present in advanced stages where in chemotherapy achieves a response rate of mere 30% (approx) and a median survival of less than a year, off-course sometimes with concerning side effects. Biologically this tumor is driven by epidermal growth factor (EGF) signaling which bind to the receptors present on the cancer cells and promote tumor growth. Drugs blocking this signaling such as “Gefitinib & Erlotinib” have shown efficacy in lung cancer patients. These drugs are available as a pill and need to be taken once a day, making therapy simpler and free of serious side effects. However, all did not seem to benefit still, which led scientist to study the ones in whom it worked the best. After studying the genetic make up of the EGF receptor of tumor cells it has been identified that those carrying specific mutations [exon 19-21 & L858R] are the ones who show extraordinary response rates to the tune of 70-75% and a median survival reaching 3 years, practically unheard of in lung cancer. On an average approx 30% patients with lung cancer may harbor these mutations; hence laying strong ground for their testing before initiating therapy with toxic chemotherapy and thus, extending the benefit of this relatively non-toxic and much superior therapy to our patients. We are now regularly doing these tests in eligible patients of lung cancer. Another target lately identified in lung cancer which has attracted ardent interest in the oncology community is cancer gene EML4-ALK which if positive responds to a new research molecule Crizotinib, again in a pill form, with similar encouraging response rates. My second example is colon cancer, the third most common cancer world wide. Again EGFR targeting drug (Figure 1) had found its utility in therapy of this disease. More detailed research showed that it works the best in patients who lack mutations in K-ras which is an onco-gene. This is exactly the opposite situation to above, were in absence rather than presence of mutations defines sensitivity to the drug. Response rates of 40-50% with chemotherapy alone has increased to 70% with addition of this EGFR targeting drug called “Cetuximab”, thus providing a new lease of life to patients of colon cancer. Many more such examples exist today. It is worthy of mentioning. that oncology has seen a great deal of advancement in the last decade. We are now being able to customize our treatment according to the tumor type, at least in some cancers. However, there is a lot which needs to be done. We have witnessed the era of targeted therapy and now we are all set for the new beginning - the era of personalized treatment.