EFTA02676840.pdf

The Final Frontier? Inhibitor Cocktails to Stamp out Cancer The use of mutation-specific. inhibitor drugs to fight cancer has been growing in popularity around the world. In fact. over the last ten years. the prescription rate ofinhibitors over cytotoxic chemotherapy has more than tripled according to the National Institute ofCancer. Indeed in 2004. the Journal ofOncology published a revealing table with cytotoxic chemotherapy as the sole treatment: the 5-year survival rate was on avenge. less than 2.2% for hundreds of thousands ofpatients across twenty-two cancer types: the most being 41%. the least, eero. The statistim, though challenged from every comer, were not surprising considering that cytotoxic chemotherapy is a direct derivative of mustard gas. a WWI and WW 2 chemical warfare agent. I lowever. while inhibitors are increasingly and remarkably effective in reducing tumors and cancer cell counts in a short amount of time, and with a fraction of the toxicity compared to their chemotherapy counterparts, cancer resistance to inhibitors remains an ongoing problem. Inhibitor drugs are molecules that bind uniquely to a cancer cell's surface and block an aspect of that cell's functionality. For example. PARP inhibitors, designed to stop breast cancer, bind to an enzyme pathway found distinctly on breast cancer cells with a BRAC genetic mutation. The PARP molecule's attachment prevents the cell from performing DNA repair. leading to its death. What has baffled doctors however, is that after remission from inhibitor therapy, a resurgence of cancer almost always occurs and often at a more aggressive rate. Over the last several years, doctors have tackled the problem by treating patients with a secondary inhibitor, only to find secondary resistance and with a patient, more debilitated by the continuous use of drugs and emergence of aggressive cells. it's becoming clear to the medical establishment that a cocktail of inhibitor drugs need to be given simultaneously." remarked. founder of the Program for Evolutionary Dynamics at Harvard University. The department or PED, studies the evolution of microbiology with the use ofmathematics, including viruses and diseases such as cancer. A New York financier and science philanthropist, funded the PED's huge strides in detailing cancer resistance to inhibitor drugs. Under the direction of Martin Nowak. a Biology and Mathematics Professor at Harvard, the PED designed mathematical models showing exactly how a minority of mutated cancer cells are either immune from the start of treatment, or evolve through reproduction, to become immune to an inhibitor drug. Their models also showed how even a single mutated cell can quickly evolve to tumor level. For example, approximately half ofnon-small cell lung cancer cases with mutations to EGER TX inhibitors became resistant from a single mutation of the protein T790M within the EGER kinase domain. PED's work caught the attention ofIle. Bert Vogelstein, the lYinzetor of the Ludwig Center for Cancer Genetics and 'Therapeutics at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University School of Medicine. Dr. Vogelstein was studying resistance to a colon cancer inhibitor called panitumumab. Enlisting Dr. Nenvak's help. Vogelstein and the PED designed a mathematical model from the tumorous tissue of 28 colon cancer patients at Johns I Iopkins about to embark on a course of paninunumab treatment. Nowak's findings were extraordinary: they showed that even before treatment began. less than .0001% ofcells carried resistance to the inhibitor but could quickly evolve over the course of a year to predominance and tumor level. Based on these findings, amongst others, Dr. Vogelstein and II,. Nowak concluded that a cocktail of inhibitor drugs and in the right proportion. must be used to target all colon cancer mutations. The challenge however is daunting: each cancer requires its 0%11 tailor-made inhibitor. and within each tumor, various inhibitors arc needed to target the variety ofmutations. For example. gastric adenocarcinomas, stemming from amplification of the growth factor receptor gene c-MET, only respond to novel inhibitors of the MET tyrosine kinase. leading to the initiation of a genotype-directed clinical trial. The FDA has approved a handful of inhibitors, but many more arc needed. To date, the survival rate for fully metastasized pancreatic is still only 2%, metastasized lung: 4%, melanoma: 16%, colon: 12%. and distant metastasized breast: 24%. Secondly, there arc few if any, clinical trials that offer inhibitor combinations: the concept is still novel and most pairings with other drugs tend to be with cytotoxic chemotherapies since finding to a large degree comes from the pharmaceutical companies, seeking to prolong their inventories' shelf- life. Less cynically, countless trials pandit& that cytotoxics in conjuntive therapy with inhibitors can, with certain cancers. increase survival by a month or two. EFTA_R1_01970209 EFTA02676840 "A third major challenge to developing inhibitor cocktails is the need for better mutation analysis," out, whose foundation, the Jeffrey Epstein VI Foundation. hinds mining edge cancer research around the world. PED's studies have shown that meta solid tumors contain 40 to 100 mutations and that only 5 to IS of these at any given time actually drive tumor growth. Isolating these mutated driven via biopsy however can be onerous on the patient, particularly if the biopsy is extracted from an organ. lung or boot and if it has to be repeated over time. Looming on the horizon is the promising CTC circulatory tumor cell microfluidic chip test, a blood test developed at Massachusetts General that can isolate and identify cancer mutations at any given time. To date, the test has identified more than 1,200 cancer-causing genetic mutations, the largest collection in the world, but the test is not yet FDA approved, nor is it available in any clinical trials. Lastly, combination proportions will need to be determined as cocktail inhibitor trials become the norm, and that of course, will take time. EFTA_R1_01970210 EFTA02676841