Jeffrey Epstein Philanthropy
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The Program for Evolutionary Dynamics and the Jeffrey Epstein VI Foundation Support the novel use of Inhibitor Cocktails for 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 clinical use of inhibitors over cytotoxic chemotherapy has more than tripled according to the National Institute of Cancer.  Cytotoxic chemotherapies are simply not targeted enough to most cancer cells and still too detrimental to the body as a whole. Indeed, in 2004, the Journal of Oncology published a revealing table with cytotoxic chemotherapy as the sole treatment: the 5-year survival rate was on average, less than 2.2% for hundreds of thousands of patients across twenty-two cancer types: the most being 41%, the least, zero. The statistics, though challenged from every corner, were not surprising considering that cytotoxic chemotherapy is a derivative of mustard gas, a WW1 and WW 2 chemical warfare agent.

However, 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 manufactured molecules that bind to an enzyme unique to a cancer cell 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.  The whole concept is a bit like, ‘death-by-Tetrus.’

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,” Jeffrey Epstein remarked, founder of the Program for Evolutionary Dynamics at Harvard University. The department or PED, studies the evolution of microbiology with the use of mathematics, including viruses and diseases such as cancer.

Under the direction of Martin Nowak, an eminent evolutionist and Biology and Mathematics Professor at Harvard, the PED made huge strides in detailing cancer resistance to inhibitor drugs. Over the last five years, Nowak and his team created mathematical models showing how a minority of mutated cancer cells are either immune from the start of treatment, or evolve through reproduction, to become resistant to an inhibitor drug. Their models also showed how even a single mutated cell, with the slightest variation, can quickly evolve to tumor level. For example, approximately half of non-small cell lung cancer cases with mutations to EGFR TK inhibitors became resistant from a single mutation of the protein T790M within the EGFR kinase domain and developed to tumor level within nine months.

PED’s work caught the attention of Dr. Bert Vogelstein, the Director 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. Nowak’s help, Vogelstein and the PED designed a mathematical model from the tumor tissue of 28 colon cancer patients at Johns Hopkins about to embark on a course of panitumumab treatment.

Nowak's findings were extraordinary: they showed that even before treatment began, less than .0001% of cells 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 Dr. Nowak concluded that a cocktail of inhibitor drugs and in the right proportion must be used to target all colon cancer mutations.

Cocktails of cancer inhibitors are creeping into the market. Just a few years ago, the FDA approved the first combined cancer inhibitor drugs as a single pill.  Prior to that, the FDA required that the merit of each active ingredient be proven before it could be added to another.  And just a few months ago, the FDA approved the first combined inhibitor therapy pill for melanoma:  Dabrafenib and trametinib, designed to block certain BRAF enzyme pathway genetic mutations. These mutations occur in approximately 50% of melanoma patients and can be identified with a diagnostic test.

Fighting HIV resistance with preemptive cocktails has thankfully become the norm around the world. However, the FDA has taken much longer to acknowledge the overwhelming evidence that each cancer type, like the HIV virus, can produce predictable secondary mutations. Part of their delay perhaps, stemmed from the financial priority (within the agency and from outside) given to promoting existing chemotherapies. Cancer is, after all, a much older market than HIV, with a history of less effective drugs needing a resurrected or prolonged shelf life as a conjunctive partner with the new inhibitors.

So far, combined cancer inhibitors have shown promising results. After one year of clinical trial treatment on the combined pill, Dabrafenib and Trametinib, 41% of melanoma patients showed no resistant growth compared with only 9% in the monotherapy Dabrafenib arm. The inhibitor combination also reduced the resistant emergence of secondary cutaneous squamous cell carcinoma, down to 2% from 19% in the Dabrafenib monotherapy group.

The FDA’s accelerated approval of combined inhibitor drugs for cancer will turn the industry on its head: pharmaceuticals such as Roche and GlaxoSmithKline can now actively put money towards developing such pills and funding trials to support them.
Currently for example, GlaxoSmithKline is sponsoring clinical trials that compare inhibitor combinations for colon cancer: dabrafenib/panitumumab and dabrafenib/trametinib/panitumumab combinations compared to a 5-fluorouracil-based chemotherapy.

The cocktail approach is still daunting: each cancer requires its own tailor-made inhibitor. 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. And within each tumor, various inhibitors could be needed to target the variety of mutations.  Studies from the Program for Evolutionary Dynamics showed that most solid tumors contain 40 to 100 mutations and that as much as 5 to 15 of these can drive tumor growth at any given time. Indeed, Dr. Scott Kopetz, associate professor of gastrointestinal oncology at MD Anderson Cancer Center, amongst others, affirmed that targeted inhibitor cocktails seem to be most effective for blood and immune-cell cancers such as chronic leukemias; since their mutation pool is more homogenous. Breast, prostate and lung tumors however, contain a wider heterogeneity of mutations, making them more challenging to tackle with a cocktail.

Secondly, there are still few clinical trials that offer inhibitor combinations: the concept is still novel and most pairings with other drugs, if any, still tend to be with outdated cytotoxic chemotherapies. Today, the FDA has approved a handful of inhibitors, but many more are needed. According to the National Institute of Cancer, the 5 year survival rate for fully metastasized pancreatic is still only 2%, metastasized lung: 4%, melanoma: 16%, colon: 12%, and distant metastasized breast: 24%.

A third major challenge to developing inhibitor cocktails is the need for easier mutation analysis. Isolating mutated tumor drivers via biopsy can be onerous on the patient, particularly if the biopsy is extracted from an organ or bone and if it has to be repeated over time. Looming on the horizon however 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; in genetic real time so to speak. 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.

Also needed is improved 3-dimensional digital imaging of a mutated cell’s enzyme pathways to better see what molecules can be used uniquely as an effective blocker, while not harming healthy cells.  Today about 90% of enzyme analysis is still done with X-Ray crystallography, but is rapidly moving towards the higher resolution of nuclear magnetic resonance, cryo-electron microscopy and proteolysis, useful for more crystallizable  proteins.

Lastly, combination proportions need to be determined as cocktail inhibitor trials become the norm. And that of course, like everything else, will take time.

We cannot yet say bottoms up to defeating cancer with a tailor-made inhibitor martini, but the industry, if it navigates a swift, ethical course, is well on its way.


SOURCE:
www.jeffreyepstein.org






        

 






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