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Calithera Targets Otherworldly Metabolism of Tumor Cells

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conducting two similar trials in humans—one in advanced multiple myeloma and non-Hodgkin’s lymphoma, and another in patients with acute leukemias. The main aim of the trials is to assess the safety of CB-839 doses at different levels. But the company will also be looking for signs of anti-tumor responses—which could point to the cancer types best suited for larger trials.

Molineaux expects that CB-839, if approved as a treatment, is most likely to be used to bolster the effects of other anti-cancer drugs as part of a combination therapy. But the ongoing Phase I trials may give some signs of what it can do alone, she says.

“We’re certainly giving the drug a chance to show us single-agent efficacy,” Molineaux says. “If we see that, it puts a big spotlight on which indications to pursue.”

Other companies have also been designing small molecules to disrupt the deviant metabolic pathways of tumor cells—they include Cambridge, MA-based Agios Pharmaceuticals (NASDAQ: AGIO); Advanced Cancer Therapeutics of Louisville, KY; Cranbury, NJ-based Cornerstone Pharmaceuticals; and London-based Cancer Research Technology, which is collaborating with UK pharmaceutical company AstraZeneca.

One class of drugs has already been approved to starve cancer cells that are dependent on the amino acid asparagine. The drugs are genetically engineered enzymes called asparaginases that break apart molecules of asparagine in the bloodstream. The drugs, which include pegaspargase (Oncaspar) from Sigma-Tau Pharmaceuticals of Gaithersburg, MD, and Dublin, Ireland-based Jazz Pharmaceuticals’ asparaginase Erwinia chrysanthemi (Erwinaze), are used in combination therapy regimens to treat acute lymphoblastic leukemia.

Two US companies are now vying to develop genetically engineered enzymes that deprive tumors of the amino acid arginine: San Diego, CA-based Polaris Pharmaceuticals and Austin, TX-based Aeglea BioTherapeutics.

Calithera was originally founded in 2010 to develop cancer drugs based on the work of UCSF professor Jim Wells, who had figured out how to activate enzymes called caspases that help kill cancer cells. But in less than a year, the tactic proved to be unworkable as a treatment strategy, Molineaux says; Wells found that the caspase activators spurred the formation of spaghetti-like complexes that couldn’t easily penetrate cells. Faced with that curveball, Calithera struck off in a whole new direction to pursue tumor starvation tactics. Some of the investors who had pledged a hefty $40 million to get Calithera started have continued to support the company in its new effort to investigate anti-tumor metabolism drug strategies.

In late 2013, Calithera completed a $35 million Series D financing led by new investor Adage Capital Partners, along with prior investors Morgenthaler Ventures, Advanced Technology Ventures and Delphi Ventures. The Longwood Fund is also among the new investors. Calithera has raised a total of $63 million since its founding, Molineaux says.

The recent fundraising round will keep Calithera going for about two years—long enough to complete its Phase I trials of CB-839, Molineaux says. The company hopes to announce its first data this year, and release most of the remaining results in 2015.

But the 35-employee company isn’t confining itself to anti-cancer programs based on tumor starvation. In preclinical studies, Calithera is also developing inhibitors of a protein called Mcl-1, which is suspected of helping cancer cells to avoid falling prey to a programmed process of cell death called apoptosis.

Molineaux says Calithera has many collaborations with academic research groups, and is on the hunt for more new cancer targets and experimental drug agents that could be refined by its medicinal chemistry team.

“We’re casting a wider net,” she says.

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