In previous columns of The Currently Incurable Scientist, we’ve gone over a number of different types of colorectal cancer (CRC) experimental therapies – from targeted agents to various flavors of immunotherapies. In this installment, I want to introduce you to yet another area of intense cancer drug research, and the example I will use to illustrate this research area is an experimental drug named “RRx-001,” currently in a randomized Phase 2 trial for CRC.

Epigenetics – a Software of Life

First, a definition (thankfully just one, unlike my last column!) You’ve heard of the DNA genetic code, but what are “epigenetics”? You know I love analogies – I am going to use a great one I found in this paper. You can think of epigenetics as software running on top of the DNA; software which tells genes when they should turn on and off. And as “software”, it can be easily modified and adapted – as any of you receiving constant cell phone app updates know all too well!

Epigenetics and Cancer

As tumors grow, they are constantly finding new tricks to survive and grow in places where they really shouldn’t be. For example, there is no natural reason for a piece of colon or rectum to start growing in your lungs! The tumors are attacked by the immune system, they are attacked by chemotherapy, yet they persist to grow in environments which are not made for them. To survive all these “hostile forces”, one of the things tumors use to survive are epigenetic modifications. When it comes to cancer, epigenetics play an exceedingly important role on multiple levels including:

• Turning genes on which tell a cancer cell to grow when it shouldn’t be growing
• Turning genes off which normally would tell a cancer cell to stop growing or die
• Turning genes off/on which help the tumor evade the immune system
• Turning genes off/on which cause tumors to become resistant to chemotherapy

All of these aspects are important but due to the short length of this column, I’m going to focus on that final point: Turning genes off/on, which cause tumors to become resistant to chemotherapy. You may know patients who initially responded to a commonly used chemotherapy for CRC, FOLFIRI, but who eventually became resistant. One potential way for this resistance to arise is via epigenetic changes in the tumor, allowing it to escape the chemotherapy onslaught.

RRx-001 – A Novel Epigenetic Modifying Drug

Drugs targeting epigenetics have been in the clinic for several years – but today I wanted to focus on a relatively new one with a very unique and intriguing preliminary clinical profile: RRx-001. RRx-001 is unique in various ways. First of all, unlike most epigenetic drugs it impacts multiple epigenetic pathways, instead of selectively impacting only one or another. It also is unique in that RRx-001 is activated by low oxygen (“hypoxic”) areas (which are often the case inside tumors) and in fact, tumor hypoxia is increased by RRx-001 itself, leading to a chain reaction.

Potential Resensitization to Chemotherapy without Standard Chemo Side Effects

RRx-001 had a very interesting preliminary clinical profile in its Phase 1 clinical trial testing which was recently published in the journal, Lancet Oncology, along with an accompanying commentary. In the small Phase 1 trial (25 patients, 11 of whom had CRC), the following “standard efficacy readouts” were seen: 14/21 evaluable patients had stable disease of at least 2 months, 7 patients had stable disease for more than 4 months and 1 patient had tumor shrinkage (a “partial response”) More intriguing however were these additional clinical readouts About half of the patients reported improved disease symptoms (3 individuals even returned to full-time work!). The only side effect seen in multiple patients at the dose currently being used in the follow-up Phase 2 trial was injection site pain. No nausea. No hair-loss. No fatigue. No low blood counts. Nothing similar to standard chemotherapy or prior epigenetic drugs’ side effects. Most intriguingly, it was observed that multiple CRC patients who had been resistant to FOLFIRI when they entered the trial were found to be no longer resistant when they were retreated with FOLFIRI after the trial. Although the number of patients examined was very small, RRx-001 appears to potentially have the ability to resensitize CRC patients towards previous FOLFIRI resistance as well as potentially doing so without major systemic side effects! In addition to the Lancet Oncology Phase 1 trial publication, two case reports on CRC patients from this trial have also been published. Even though it has not yet been tested clinically, as a scientific hypothesis, it is fascinating to ponder how many cycles of FOLFIRI -> RRx-001 -> FOLFIRI -> RRx-001… could potentially be done in a continuous loop fashion. Only clinical testing will tell if that strategy could be successful, but as a potential scientific concept, it is quite exciting to ponder! RRx-001 is currently being tested in a larger Phase 2 trial (NCT02096354) randomized against regorafenib. If the preliminary clinical efficacy and safety profile of RRx-001 is confirmed in larger trials, it could dramatically change the treatment protocols of Stage IV CRC patients. Quoting the Lancet Oncology commentary, “RRx-001 is a member of a new class of panepigenetic modifying drugs… that look exceptionally promising in early clinical development.” I couldn’t agree more! Stay tuned...   Dr. Tom Marsilje is a >20 year oncology research scientist with “currently incurable” stage IV MSS colon cancer and is a Colon Club 2016 Colondar 2.0 model. He also writes a personal blog on life at the intersection of being both a cancer patient and researcher “Adventures in Living Terminally Optimistic” and posts updates to Twitter @CurrentIncurSci. As mentioned in his introductory post to this monthly column, he is a Ph.D. scientist and not a M.D. He exclusively gives his opinions on the “science” of experimental therapies – nothing written should be misinterpreted as implying medical advice. Disclosure: My medical oncologist is the PI of one of the RRx-001 clinical trial sites.

8 thoughts on “Reprogramming a Tumor for Death”