Curious Dr. George | Plumbing the Core and Nibbling at the Margins of Cancer

AACR: Advances in Precision Medicine to Continue

Srivani Ravoori, PhD, Associate Director, Science Communications; American Association for Cancer Research

Intro: The American Association for Cancer Research (AACR) publishes a forecast blog post at the start of each year to ask prominent cancer research leaders what they envision the new developments will be in areas like immunotherapy, precision medicine, cancer prevention, and health disparities.

In this excerpt from the 2017 post in Cancer Research Catalyst, we interviewed precision medicine expert George Demetri, MD, Professor of Medicine at Harvard Medical School, Director of the Ludwig Center at Dana-Farber/Harvard Cancer Center, and Director of the Center for Sarcoma and Bone Oncology at Dana-Farber Cancer Institute. Dr. DeMetri is a founding member of the CollabRx Editorial Advisory Board and Chief Editor for CollabRx Sarcoma. Here’s what he had to say about developments in precision medicine for treating cancer – as well as his thoughts on aspects of the 21st Century Cures Act, federal support for cancer research, and the value in supporting basic science.

Q: The American Association for Cancer Research (AACR) is arguably the World’s most important professional organization of volunteers in the cancer research field. As we enter 2017, what does AACR consider the field’s greatest challenges and opportunities?

A: “The good news is that we are still uncovering virtually monogenic diseases – diseases that are driven by single oncogenic fusions or mutations,” says Demetri, a board member of the AACR. Therapies targeting single mutations, such as NTRK fusions, lead to durable and dramatic responses, he notes.For the vast majority of common cancers, however, it is not a simple monogenic problem. We need more combination therapies and more research to find where the Achilles’ heel is, Demetri says. “This is where we, as professionals, need to be careful about overstating the value of precision targeting to the public without also getting too negative.”
“Cancer diagnostics are going to get better and better,” says Demetri, and predicts that we may be on the verge of putting together a composite set of predictive and prognostic biomarkers. “Our diagnostic tools are getting so sophisticated that we can put cancers into different bins at different times in a patient’s treatment course.” With treatment, cancers acquire new mutations to thrive, and with technological advances we can now, in many cases, track the different mutations that are likely driving the disease and match them with different drugs.
While Demetri notes that we have to be intellectually honest about the fact that most patients treated with targeted therapies develop resistance, he is not yet giving up on our aim of finding cures. It may appear as not achievable now, but we are getting there through combination therapies, he adds.
We really need to hone our ability to pick combinations that are not cross-resistant and truly synergistic or complementary, he notes. One of the many approaches is to tie targeted therapies with less-targeted, more multifunctional modalities such as immuno-oncology, which can trigger the immune system. “Even though checkpoint inhibitors are a multibillion dollar market, I would say they are still in their infancy as far as our extent of understanding goes,” notes Demetri.

We are likely to see more efforts in developing very potent epigenetic drugs, according to Demetri. Drugs that target EZH1, EZH2, and bromodomain inhibitors are an alternative way to addressing the bad wiring in cancer cells, notes Demetri, who expects to see more studies testing combinations of epigenetic therapies with targeted therapies and immunotherapies.
This year, Demetri predicts, we will gain further understanding into the smaller, molecularly defined subsets of cancer, and develop even better, more precisely targeted therapies.
A recent development is the work on protein degradation technologies, which make it possible to bring the ubiquitin-proteasome system to degrade a protein of interest in a very catalytic way, Demetri says. “This could be a real game changer,” he predicts. Researchers are still trying to understand how to use the protein degradation system appropriately to target undruggable proteins such as Myc and Ras. “I think this is an exciting area of research and this year we are likely to see some proof-of-concept studies. I feel it is just about to hit the mainstream,” Demetri notes.
Progress with cancer genomic medicine depends on a key element, data sharing—large genomic datasets made available to all so the significance of the genetic alterations present in patients’ tumors could be gleaned through collective evidence. However, data sharing comes with many challenges, such as protection of patients’ privacy and ownership of the data.
Progress with breaking the barriers of genomic data sharing will come from continued advocacy from the patients rather than the professionals, Demetri says. “It is vital to leverage our interactions with patients and patient advocates who want the same things that we do to push the kind of data sharing that will advance the field.”
In the event that the efforts from the federal government to further data-sharing initiatives are insufficient, we may see the private sector jumping in to build databases, he notes. “A lot of this will depend on the next heads of the NIH and the NCI,” he adds.
Regarding the provisions in the 21st Century Cures Act to roll back FDA regulations to accelerate drug development, “I like the idea that we can streamline and simplify and have more transparency in the rules for therapeutic development in cancer,” Demetri says. “I’m optimistic that we will keep the focus on both safety and efficacy.” Ultimately, if a drug does not work sufficiently well to justify its use or if it is prohibitively expensive compared to other equally effective options, Demetri says he would trust our community of professionals would have the integrity to not use it, and to explain these choices and options to our patients.
We are in the post-genomic era where we need to overlay other elements (such as epigenetic compensatory mechanisms, metabolic or anatomic resistance mechanisms, etc.) on top of simple genotyping and basic interpretation of the genotype, Demetri says. Adding this is more complicated and will take a lot of effort and money to fund the necessary research. “I feel that the advances against cancer are very powerful and will go forward no matter what, but the question is, how fast can we get there and at what scale and scope?” Demetri asks.
“Reading the tea leaves of the new administration, we may be facing less than optimal federal support for cancer research, but I’m hopeful that we will see more private sector-based and philanthropy-based partnerships that will step up to support cancer researchers at this important juncture,” Demetri says.
“What I’d like to see this year is some time for positive reflection to realize the importance of public funding of science, which is tied to the importance of funding investigators who can follow their instincts to make new discoveries,” says Demetri. He adds, “Fundamental, curiosity-driven research is the only way we are going to get to unthinkable breakthroughs – real paradigm shifters akin to kinase inhibitors in the late 90s and immuno-oncology drugs more recently.”
“We need to recognize that there is a social good to funding basic research: without fundamental scientific understanding, applied medical research is limited to moving already existing therapies around the chessboard. We need science-based novel agents and new approaches to change the therapeutic approach and help patients in ways we might not be able to conceive of today,” Demetri notes and adds, “We have not told that story well enough and I’d like 2017 to be the year where we make that a little clearer to the public so there’s more support for basic science. That is critical.”

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