The astronauts rejoiced after their safe landing on the planet they’d come to transform into Earth’s first space colony. But within a few weeks, their leader was struck with a disturbing malady. More and more, his cells were taking on strange traits seen in a one-celled fungus that people on Earth called “brewer’s yeast.”
By the time this story, or one like it, is actually written, doctors may know how to cure the space leader’s affliction. Drug developers on Earth are already working on it. The disease is not some invasion by alien parasitical fungi, and it’s certainly not new to humankind. It’s called cancer.
As far back as the early 1920’s, scientists were finding oddball traits in the energy metabolism of tumor cells. In recent years, cancer drug developers such as South San Francisco, CA-based Calithera Biosciences have jumped in to exploit the weird differences between the way normal cells and tumor cells process their nutrients. These metabolic changes apparently help tumor cells to multiply uncontrollably by allowing them to rapidly make all the proteins and other ingredients needed for new cells.
In 1922, the German chemist Otto Warburg (who won a 1931 Nobel Prize for other work) discovered that some cancerous cells gobbled up sugar at a far greater rate than normal cells. In their craving for sugar, and in other metabolic quirks, tumor cells have been compared to the yeast species Saccharomyces cerevisiae, a fermenting agent that people use to make beer, wine, and bread.
Because tumor cells often drive their growth through an abnormal addiction to certain molecular morsels such as sugar or amino acids, drug companies reckon that they may be able to kill the cells by taking away the foods they live for.
In early 2011, when Calithera began looking for ways to thwart the strange hungers of tumor cells, many possibilities were open, says the company’s CEO Susan Molineaux (pictured above).
“The field was in its infancy,” Molineaux says.
Although freaky metabolic pathways are often found in cancer cells, the odd patterns aren’t the same in all cancer types. Aside from devouring sugar (the Warburg effect), the cells can develop dependencies on other nutrients, such as specific amino acids. These varied eccentricities probably result from groups of genetic mutations or alterations that can be different from one tumor to the next, Molineaux says.
Calithera decided to focus on the nutrient glutamine, an amino acid that cells of many cancer types come to depend on heavily. Glutamine is a chemical starting point for the manufacture of a range of important molecules in the cell. Some tumor cells feast on glutamine and funnel it into a round of important biochemical reactions called the citric acid cycle, or TCA cycle, which is kind of like a traffic circle with lots of on-ramps and off-ramps.
The on-ramp for glutamine is a reaction that produces a related molecule, glutamate, through the work of an enzyme called glutaminase. Calithera developed a small molecule, CB-839, that can block the action of that enzyme—cutting off the supply of glutamine as a raw material for the tumor cell’s growth, multiplication, and energy production.
“We prevent the utilization of glutamine,” Molineaux says.
The theories behind Calithera’s drug strategy gained support in lab studies. When the company tested CB-839 in tumor cell cultures of certain blood cancers and solid tumor cancers, it slowed the growth of cell populations. It also caused die-offs of some tumor cell types, including triple-negative breast cancer, an aggressive, hard to treat disease that makes up 10 to 20 percent of all breast cancers. This type of breast cancer tests negative for estrogen receptor, progesterone receptor, and HER2/neu, and is therefore insensitive to drugs that target those biomolecules. (In turn, estrogen-dependent breast cancer is less sensitive to Calithera’s CB-839 than triple-negative breast cancer.)
Studies of CB-839 in animals also showed anti-tumor activity in cancers including triple-negative breast cancer. Lab studies showed that growth in this form of breast cancer seems to be dependent on the use of glutamine as a metabolic fuel, and displays high activity of the enzyme glutaminase. Calithera is now looking for biomarkers that would flag the distinct types of cancer most likely to respond to its drug.
In late February, Calithera began its first early stage trial of CB-839 in participants with advanced solid tumors. The company is also 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.