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Cancer Commons & xCures, AI-Based Virtual Trial Companies, Invite Participation from Patients Who Try New Combination Therapy for Pancreatic Cancer; Highly Promising Results Just Published in Nature Medicine; Relevance to TV Game Show Host Alex Trebek

Treatment for metastatic pancreatic cancer (pancreatic ductal adnocarcionoma or PDA) has seen progress in recent years, but outcomes remain poor and treatment advances that can prolong patients’ lives, even for a few months, are eagerly awaited. Two papers, just published online on March 4, 2019 in Nature Medicine (https://www.nature.com/articles/s41591-019-0368-8) (https://www.nature.com/articles/s41591-019-0367-9), suggest that a new combination of two existing drugs (an autophagy inhibitor and an inhibitor of the downstream metabolic pathway activated by mutated KRAS), which are both already FDA-approved for other conditions, may significantly delay progression of pancreatic cancer in human PDA cells in vitro and in PDA-derived tumors in mice. Furthermore, the first patient treated with this combination experienced a prolonged response that lasted almost six months. In light of these promising results, Cancer Commons (https://www.cancercommons.org/) is partnering with xCures (https://www.xcures.com/) to track the experiences of patients who choose to try this new combination therapy. This effort is particularly relevant given the March 6 announcement by TV Jeopardy game show host Alex Trebek that he has been diagnosed with stage 4 pancreatic cancer. The two Nature Medicine studies came from The Huntsman Cancer Institute at the University of Utah and from the Lineberger Comprehensive Cancer Center at the University of North Carolina at Chapel Hill. Cancer Commons, founded by metastatic melanoma survivor, and former high-end electrical engineer and artificial intelligence expert, Marty Tenenbaum, PhD, (https://www.cancercommons.org/about/our-founders-story/), is a nonprofit network of patients, physicians, and scientists from many disciplines. Participants identify the knowledge needed to get the best possible outcomes and continuously refine this knowledge based on clinical results and breaking research. Specifically, Cancer Commons focuses on providing expert, compassionate, one-on-one guidance to patients and families struggling with cancer of any type or stage. The organization fosters a network of leading physicians, molecular tumor boards, cancer researchers, and computer scientists to leverage one another’s expertise and resources, and empower the global community to share data and knowledge. Cancer Commons provides relevant knowledge from top experts and from similar patients so that patients and their caretakers can make better, more informed treatment decisions. The organization continuously validates and refines the world’s collective cancer knowledge, based on patients’ clinical results and the latest research.

CANCER COMMONS OFFERS POWERFUL ADVANTAGES OVER TRADITIONAL CLINICAL TRIALS

In the era of molecular medicine, advanced cancers are characterized by thousands of genetic alterations, potentially creating tens of thousands of clinically distinct subtypes. Moreover, there are hundreds of approved therapies, which have never been tested head to head, or in combinations. Conventional clinical trials cannot efficiently search this huge combinatorial space.

In the absence of definitive clinical studies, the best way to help current patients is by aggregating and validating the insights, intuitions, and experiences of our best clinicians. By capturing the unique experiences of patients being treated at top centers with investigational drugs and cocktails, Cancer Commons will enable the entire cancer community to learn, much more efficiently than by traditional clinical trials, the best way to treat similar patients wherever they are seen.

Given the wide variation in cancer treatment and outcomes across institutions, Cancer Commons is convinced that its efforts to learn from the best and communicate that knowledge to the right patients and physicians at the right time will save innumerable lives, even without new blockbuster drugs.

Cancer Commons believes that only a patient-centric non-profit like itself, committed to connecting and leveraging everyone touched by cancer, can hope to overcome the widespread aversion to data sharing and collaboration that pervades the medical establishment.

XCURES

xCures is a for-profit company, co-founded by Dr. Marty Tenenbaum and Jeff Schrager,PhD. Dr. Schader has over 20 years of experience in applying high-performance cloud computing and machine learning in biological science. xCures is reinventing oncology through the use of virtual trials that continuously learn from all patients, on all trEatments, all the time.

xCures is partnered with THE non-profit companies Cancer Commons and The Musella Foundation For Brain Tumor Research & Information, Inc. (https://virtualtrials.com/musella.cfm).

The CEO of xCures is Mika Newton (https://www.linkedin.com/in/mikanewton/). Mr. Newton has over twenty years of leadership experience in the life sciences. Most recently, he was the Chief Commercial Officer of Doctor Evidence, LLC. Prior to Doctor Evidence, he was the General Manager of Clinical Development Services at diaDexus, SVP of Client and Market Development at Evidera, VP of Sales and Marketing at Archimedes, and held sales management and sales operations roles at Quintiles, Invitrogen, and Tripos.

Virtual trials represent an AI-based rethinking of the way treatments and tests are validated. An extension of prospective Bayesian adaptive trial designs, virtual trials are the most efficient, cost-effective, and ethical clinical testing method available, covering all patients and all treatments, with no exclusion criteria. Virtual trials enable the efficient large-scale testing of breakthrough drugs and multi-drug regimens that would otherwise be too economically risky.

Every year, many thousands of cancer patients die unnecessarily because their doctors don't know the best way to apply the available tests and treatments. Moreover, it takes far too long, and costs far too much to bring new tests and therapies to the clinic. The most effective treatment protocols involve intelligently designed, individually tailored, sequences and combinations of tests and drugs, but there are many more plausible regimens than can be efficiently tested in the current clinical trials paradigm. Patients who have exhausted the standard of care are routinely treated with off-label drugs, rational cocktails. Unfortunately, these individualized experiments are not coordinated, and their results are seldom reported, so little is learned from these.

xCures is developing an AI-based methodology and platform to run “Virtual Trials,” which continuously learn from the clinical experiences of all patients, on all treatments, all the time. Each patient's treatment regimen is adaptively planned by a “Virtual Tumor Board” optimize the individual patient’s outcome. The Virtual Tumor Boards share treatment recommendations and rationales with each other and with leading academic cancer centers through a Knowledge Network. Algorithms coordinate these individual treatment plans across all patients in the network to continuously optimize collective learning.

By tightly integrating clinical research and care, xCures enables physicians to make better treatment decisions, pharma/biotechs to develop drugs at a fraction of the time and cost of traditional trials, and patients to receive superior outcomes. This integration replaces traditional clinical trials with a rapid learning system where every treatment and decision contributes to our understanding of cancer biology and therapy.

xCures believes its unique approach simultaneously offer significant and unique benefits to patients, physicians, pharma/biotech, and researchers.

First, virtual trials are uniquely patient-centric; Each patient is assured of getting the best treatment options from the best experts supported by the best algorithms. There are no exclusion criteria and no randomized controls.

Second, physician are empowered to offer their patients access to the best off-label or investigational drugs available through trials or expanded access. Physicians can participate in clinical research through case series and Investigator Initiated Trials.

Third, the pharma/biotech sector can test drugs far faster and more cheaply utilizing far fewer patients, than is possible in either traditional trials or even in contemporary adaptive trials. Pharma/biotech can obtain direct feedback from leading physicians and manage compassionate use, expanded access, and right-to-try requests in a patient-friendly way, and capture regulatory-grade, real world evidence.

Fourth, researchers are enabled to bridge clinical research and patient care; they can access real-time patient data and contribute treatment hypotheses based on their latest research, and have these hypotheses efficiently validated.

COMBINATION THERAPY FOR PANCREATIC CANCER & ALEX TREBEK

Cancer Commons and xCures believe that this very recent breakthrough in pancreatic cancer research, reported in the two Nature Medicine articles, offers an excellent opportunity to implement the companies’ unique, paradigm-shattering approach to obtain concrete patient-centered results. As noted earlier, such an approach was given especial relevance with the March 6 announcement by TV Jeopardy game show host Alex Trebek’s announcement that he has been diagnosed with stage 4 pancreatic cancer, which is typically rapidly and uniformly fatal.

The two studies just published in Nature Medicine both suggest, based on the results of slightly different experimental approaches, that the combination of two existing drugs, one that inhibits the orchestrated process of autophagy and the other that inhibits the downstream metabolic signaling pathway activated by the mutated oncogenic protein KRAS, offers the prospect of having significant positive results in the treatment of pancreatic cancer, which, as noted earlier, has, thus far, proven resistant to all known treatments.

MORE DETAIL ON NEW RESULTS PUBLISHED IN NATURE MEDICINE

Below are more details on the exciting results reported in the two Nature Medicine articles.

Most pancreatic cancers have a mutation in a gene called KRAS. Mutated KRAS activates and signals other proteins to drive cancer progression. Creating a drug to inhibit KRAS itself has proven to be very difficult, so most efforts to inhibit KRAS have focused instead on downstream proteins that are activated by KRAS, of which MEK and ERK are two that are easier drug targets.

However, MEK inhibitors have shown little activity in KRAS-mutant cancers, and, while ERK inhibitors are in clinical trials for KRAS-mutant cancers, they don’t have a deep or lasting effect on their own. Hence, a combination approach may achieve a greater effect in pancreatic cancer.

Many KRAS-driven cancers depend on autophagy, a highly structured and orchestrated “recycling” process by which cells break down damaged organelles and macromolecules, and then can reuse their building blocks to maintain themselves.

The two March 4 publications in Nature Medicine report that inhibition of MEK or ERK with targeted drugs surprisingly increases autophagy. In particular, the Utah group showed that inhibition of KRAS→RAF→MEK→ERK signaling elicits autophagy, a process of cellular recycling that protects PDA cells from the cytotoxic effects of KRAS pathway inhibition.

Hydroxychloroquine (HCQ) is an old FDA-approved drug used to treat malaria, and it inhibits autophagy. Based on the discovery of autophagy’s significance in pancreatic and other KRAS-driven cancers, and the drug’s availability, HCQ was previously tested in clinical trials for pancreatic cancer, but it did not have an impact when used alone.

When the authors of the current study done at the Huntsman Cancer Institute University of Utah, tried combining HCQ with MEK or ERK inhibitors, they saw a much stronger inhibition of human PDA cells in vitro and in PDA-derived tumors in mice.

Based on such compelling pre-clinical data, after fully informed consent and following institutional policies, the Utah investigators began treatment with HCQ and the MEK inhibitor trametinib in a single male patient with pancreatic cancer, who had exhausted other treatment options.

The scientists were elated to see a rapid response, with 50% reduction in tumor burden as seen on scans, and a profound drop in the tumor marker CA 19-9. The dramatic response, accompanied by a reduction in pain level, lasted for several months before resistance emerged. It is unknown whether this combination will be effective in other patients with advanced pancreatic (or other solid) cancer, but it must be tested, Cancer Commons believes.

This is an exciting advancement with two already-approved drugs, which provides patients and their physicians with the opportunity to try this combination “off label” if another proven option is not available. There may be challenges with the cost and insurance coverage, but by working with his/her physician and the pharmaceutical company assistance programs, the patient may gain access to treatment.

CANCER COMMONS INVITES PATIENTS TO PARTICIPATE IN OBSERVATIONAL STUDY

Cancer Commons always favors participation in clinical trials when possible. Currently, this pancreatic cancer drug combination is only available in one small clinical trial at the University of Utah. If access to this ongoing clinical trial and/or other standard-of-care treatments is unsuccessful, the compassionate use of this combination may be an option for patients and physicians to discuss.

Cancer Commons strongly suggests that if you and your physician are contemplating treatment with this new combination therapy, please consider being part of the Cancer Commons observational study being carried out in partnership with xCures.

As part of this tracking study, patients can share their experiences and learn from the experiences of others regarding dosing, timing, and strategies for overcoming resistance. If a better treatment comes along, you’ll be the first to know!

To register for this tracking study, please click here (https://share.hsforms.com/1M57I65HJRiSlpWo89E-WMg33u1s) and benefit from the experience of all patients by collectively exploring this promising development.

[Cancer Commons press release] [Pancreatic Cancer Action Network press releaes] [Huntsman Cancer Institute press release]

[Nature Medicine article (Utah) "Protective Autophagy Elicited by RAF→MEK→ERK Inhibition Suggests a Treatment Strategy for RAS-Driven Cancers"] [Nature Medicine article (UNC) "Combination of ERK and Autophagy Inhibition As a Treatment Approach for Pancreatic Cancer"]

[Science Daily article] [Deseret News] [Technology Network article]

ALEX TREBEK PANCREATIC CANCER STORIES

[NY Times article] [Forbes article] [USA Today article] [NPR article] [WebMD article] [CBS Boston article] [Daily Beast article]