Fine-tuning cancer medicine

1 February 2018, 11:45 am

Details matter — perhaps most noticeably in the fight against cancer. Some patients respond to a given anticancer therapy, and some do not. A new initiative at MIT takes aim at those details, and the name of the game is precision.

The recently launched MIT Center for Precision Cancer Medicine (CPCM) is housed within MIT’s Koch Institute for Integrative Cancer Research and headed by physician-scientist Michael B. Yaffe, the David H. Koch Professor of Science and professor of biology and biological engineering. The center brings together leading Institute faculty members to focus on key research themes to accelerate the clinical translation of novel cancer discoveries, treatments, and technologies.

Engineering approaches to the clinic

While other institutions have begun efforts in precision medicine as well, the MIT Center for Precision Cancer Medicine stands out for using engineering approaches to solve complex clinical challenges in cancer treatment that are rooted in biology. In particular, the CPCM combines understandings of biological circuitry — along with engineering, computational, and mathematical techniques (as well as genomic ones) — to focus on signaling networks and pathways that are aberrantly regulated in cancer cells. This strategy is supported by the fact that most state-of-the-art molecularly targeted cancer therapies are focused on these key pathways.

At its core, the CPCM is driven by both internal and external collaboration, and is devoted to translational research to help the substantial number of patients who do not respond well to traditional cancer therapies — for example, those with triple-negative breast cancer, ovarian cancer, non-small cell lung cancer, or advanced prostate cancer.

To improve outcomes for these patients, CPCM investigators are focused on four key areas of research. First among these is identifying and targeting the processes, signals, and mechanisms that determine an individual patient’s response to chemotherapy. Recent discoveries by CPCM researchers include mechanisms that cancer cells use to repair chemotherapy damage that should have killed them, to hide from drugs in protected “niches” in the body, or to grow when and where they should not.

CPCM members are also working on a second research pillar, which involves finding ways to use existing FDA-approved cancer drugs more effectively, particularly in carefully designed combinations. Combination therapies are currently used in the clinic to treat some cancers, yet the discovery process for these has been largely empirical. By contrast, CPCM investigators are integrating their knowledge of cancer biology, understandings of drugs’ mechanisms of action, and sophisticated analytical techniques, to identify or design specific combinations that work synergistically to disarm and then destroy cancer cells.

“We believe we can significantly alter cancer patients’ outcomes by determining the right combination of therapies and the right sequence of drugs for the right patients,” says Yaffe. “We’re also concentrating on innovative ways to give these drugs, like time-staggered dosages and nanoparticle delivery.” He notes that, as part of their analyses of drugs and combination regimens currently administered in the clinic, CPCM members expect to identify combinations of drugs that are not as efficacious when given simultaneously as when given sequentially, at specific intervals. Yaffe stresses that these will be important findings that could help reduce the toxicity of treatment by not exposing people to multiple drug toxicities at the same time.

In parallel with their efforts to use existing drugs more effectively, CPCM investigators are also working to identify compounds, materials, and approaches that can engage key “undruggable” genetic and molecular targets and disrupt processes driving drug resistance. The “undruggable” label often refers to the fact that a target protein or molecule lacks a site to which drugs can bind, and thus is not considered a good drug target by the pharmaceutical industry. However, using novel chemistry approaches, CPCM researchers have made early inroads against several such high-value cancer targets, including specific transcription factors and RNA-binding proteins. The center will continue and expand these efforts as the third part of its research platform, including collaborations with industry.

Finally, the fourth component of the CPCM’s efforts will be harnessing MIT’s particular expertise in big data analysis and tools to begin new and expedite existing cancer research efforts. For example, the researchers plan to use data analytics to identify selective panels of biomarkers that can be used to prioritize which of their drug combinations, treatment protocols, and formulations are best suited to a particular patient’s tumor.

Getting discoveries out the door

“Patients will be the ultimate beneficiaries of the work of the new MIT Center for Precision Cancer Medicine,” says Tyler Jacks, director of the Koch Institute and the David H. Koch Professor of Biology. “This research is, by its nature, imminently and rapidly translatable. By concentrating efforts on which patients will benefit from particular existing drugs or combinations of drugs, there is a relatively small step from laboratory to a treatment that is benefitting a cancer patient.”

While work on combinations of approved therapies, like that at the CPCM, may be more rapidly translatable than other cancer research, it can be challenging for industry to pursue, particularly when those drugs hail from multiple companies. Overcoming this disjuncture is one of the goals behind the establishment of the MIT Center for Precision Cancer Medicine, which was made possible by a generous gift from an anonymous donor.

Yaffe and his CPCM colleagues are committed to finding viable routes to move their cancer research into the clinic, particularly through collaborations between CPCM members, hospitals, and industry. Logistically, this means more work for the center’s research groups, including advanced laboratory and preclinical studies, safety and scale-up studies, and clinical-grade manufacturing, as well as staff to carry it out. Woven into these efforts, CPCM investigators will tap into MIT’s celebrated tradition of entrepreneurship and, even more so, the Institute’s expanding network of clinical collaborators. The philanthropic investment behind the center will provide stable financial support for the researchers’ endeavors.

The new hub in town

In addition to supporting the research of member investigators, the CPCM offers a robust training ground for young engineers and scientists interested in precision medicine. Moreover, it will serve as the hub of precision cancer medicine research at MIT and beyond, connecting with researchers across the MIT campus and partnering with clinical investigators in Greater Boston’s noted health care centers and around the country.

Five outstanding cancer researchers make up the center’s founding faculty:

  • Michael B. Yaffe, MD, PhD, director, MIT Center for Precision Cancer Medicine; David H. Koch Professor of Science, professor of biology and biological engineering
  • Michael Hemann, PhD, associate professor of biology
  • Angela Koehler, PhD, Karl Van Tassel (1925) Career Development Associate Professor, assistant professor of biological engineering
  • Matthew Vander Heiden, MD, PhD, associate professor of biology, associate director, Koch Institute for Integrative Cancer Research
  • Forest M. White, PhD, professor of biological engineering
Efforts are currently underway to recruit an assistant director and a scientific advisory board.

As part of its charge, and key to spurring the new collaborations in precision cancer medicine that are its focus, the MIT Center for Precision Cancer Medicine will also convene lectures, events, and scientific exchanges and symposia, the first of which is slated for the fall.

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