A look at the promising oncology therapeutics under exploration by Partners HealthCare spin-off, Raze Therapeutics.
A new approach to treating certain cancers may lie in an often-overlooked corner of amino acid metabolism, according to the science behind a new Partners spinoff. Promising oncology therapeutics under exploration by Raze Therapeutics aim to dismantle a metabolic pathway that fuels cancer's indiscriminate spread. Raze launched last fall with $24 million in Series A financing and is on track to enter clinical development as early as 2016, according to Jason Rhodes, an Atlas Venture partner and acting CEO of Raze. “For a novel area of biology, and certainly from a pharmaceutical discovery point of view with entirely novel chemistry, this is very rapid progress.,” says Rhodes. “We'll have gone from founding the company to clinical trials with first-in-class compounds in as quickly as three and a half years.” The therapeutics target a mode of amino acid metabolism known as the 1-carbon pathway, which has been studied extensively and is the target of a number of widely used but non-specific drugs, such as methotrexate. “What was not so widely appreciated is that there are two seemingly redundant 1-carbon pathways,” explains Vamsi Mootha, MD, MGH molecular biologist and professor of systems biology at Harvard Medical School, an investigator at the Howard Hughes Medical Institute, a senior associate member of the Broad Institute, and one of the company's scientific founders. “One pathway is within mitochondria, the other is within the cytosol,” Mootha says. “We still do not know why our cells need two such pathways.” Using computational genomics and metabolic profiling, Mootha's laboratory made the surprising discovery that the mitochondrial limb of this pathway is consistently elevated in a wide range of cancers. “The results are quite striking,” Mootha recalls. “Globally, this 1-carbon metabolism pathway was head and shoulders above all others in terms of being highly enriched in cancer cells.” According to Mootha, the work raises the novel idea of compartment-specific targeting of 1-carbon metabolism – an idea that could lead to safer and more effective medicines for cancer. Mootha's laboratory, based in the Department of Molecular Biology and Center for Human Genetic Research at the MGH, has made numerous advances in the field. In 2004, Mootha received the MacArthur Foundation Genius Award for his contributions to mitochondrial biology and genomics. Recent publications by Mootha and scientific founders Joshua Rabinowitz, MD, PhD, of Princeton and David Sabatini, MD, PhD, of the Whitehead Institute, have generated additional evidence for the role of 1-carbon metabolism in cancer cell growth. In collaboration with the three scientific founders, the Whitehead Institute, and Partners Innovation Fund, Atlas seeded an initial effort that quickly attracted venture backing by Atlas, Partners Innovation Fund and MPM Capital Management, MS Ventures, Astellas Venture Management, and Novartis. “With the support of the scientific founders, Raze has created a portfolio of drug discovery programs that are truly biology-driven. This focus on biology was critical for the success of Agios, a now public company, which initially targeted the adjacent area of tumor energy metabolism. We believe Raze has the potential to be as successful,” says Reza Halse, PhD, a Partner with the Partners Innovation Fund. The company is actively pursuing 10 targets of interest in the 1-carbon pathway, Rhodes notes. “Using our proprietary platform, we're able to analyze metabolic flux. We are engaged in active drug discovery and development against a number of those targets, and we're making strong progress.” Raze's rapid advance toward clinical development is exciting, Rhodes says. “It speaks to the insight and the potential of our founders' biological observations as well as to the Atlas Venture model for seeding companies and pressure-testing critical hypotheses before we launch a broader effort.” He points out that the words ‘raze' and ‘raise' have opposite meanings but stem from the same Latin root word. “We're trying to knock down cancer,” Rhodes says. “But we're doing it in a way that will raise human health.”