The Warburg effect – the marked preference of tumors for fueling themselves via anaerobic metabolism – was described more than 90 years ago.
Otto Warburg won the Nobel Prize for his discovery in 1931, and research into the phenomenon long dominated the field of tumor metabolism.
Over the past decade, however, there has been increased attention to the fact that tumor metabolism is deregulated in multiple ways beyond the Warburg effect. In addition to energy, tumor cells need large amounts of other metabolites to grow: lipids to make cell membranes and amino acids for proteins.
Researchers, meanwhile, are doing their level best to deprive them of those resources, in often innovative ways.
Amino acids: Starve tumors, or feed them junk
Tumor cells need amino acids for several different reasons. For one, rapid growth takes lots of protein.
But because tumor cells deplete their glucose for energy, they also use amino acids, in particular glutamine, as a source of carbon.
Calithera Biosciences Inc. is testing its glutaminase inhibitor, telaglenastat (CB-839), in multiple phase II trials in combination with other agents, including chemotherapy, targeted therapies and PD-1 checkpoint blockade.
In June, the company reported that in the randomized placebo-controlled phase II ENTRATA study, combination treatment with telaglenastat and Afinitor (everolimus, Novartis AG) doubled the median progression-free interval (progression-free survival, PFS) in patients with advanced renal cell carcinoma when compared to Afinitor alone. Calithera also has an arginase inhibitor, CB-1158, in the clinic.
The team at Tyme Inc., is taking an alternate approach to amino acid targeting. Rather than starving tumors, it is feeding them junk food, in the form of D-tyrosine.
D-tyrosine is the mirror image of the nonessential amino acid tyrosine in its L-form, which is the naturally occurring form. Molecules are chiral, or handed, if their enantiomers or mirror images cannot be superimposed on each other, like left and right hands.
Arguably the most famous chiral molecule in biomedicine is thalidomide, which was approved for morning sickness in 1957, only to be yanked when it became clear that one enantiomer of the drug cured morning sickness while the other caused severe birth defects.
On the over-the-counter side, the artificial sweetener aspartame consists of D-phenylalanine.
At the levels used for sweetening, D-phenylalanine does not have any ill effects. But, in principle, "your cells just don't want D – you put a D-amino acid into a protein, you just screwed up the functionality of that protein," Jonathan Eckard, chief business officer or Tyme, told BioWorld.
Tyme's SM-88 delivers a racemic mixture of D- and L-tyrosine, because the L-form is necessary to deliver the D-form to cells. Cancer cells take up more of SM-88, and in doing so, "you gum up all the tRNAs for tyrosine within the cancer cells."
SM-88 is in a multicenter phase II trial in previously treated metastatic pancreatic cancer. The company will present updated data from the ongoing trial at the European Society for Medical Oncology World Congress later this week.
Eckard said that tumors are less likely to develop resistance to "a trojan horse" like SM-88 than to an inhibitor.
"Cancer cells, if you try to restrict something, they work around it," he said – a familiar story from tyrosine kinase inhibitors.
"We are letting the cancer do what it wants. It wants amino acids," he said. The tumor cell "doesn't know that it's being poisoned, and so it doesn't try to change because it doesn't think that there's anything wrong.... There's a lower chance, logically, of resistance."
Eckard compared Tyme's approach to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), which provide faulty building blocks for DNA and RNA synthesis and are highly effective drugs for the treatment of HIV.
How tumor cells chew the fat
Lipid metabolism, too, is altered in tumor cells, though targeting approaches are earlier-stage than those aimed at amino acids.
In a tumor metabolism session at the 2019 meeting of the American Society of Clinical Oncology (ASCO), Daniel Cho, director of the developmental therapeutics program at New York University, gave an overview of recent developments in the field.
Though historically, a lot of the attention has really focused on the Warburg effect, tumor cell lipid metabolism, in Cho's estimation, is "ripe for therapeutic development."
Rapidly proliferating cancer cells, he told the audience, require higher levels of free fatty acids than their healthy counterparts for functions that include membrane biogenesis, energy production and protein modification.
Fatty acid synthase, which is a key enzyme for getting those free fatty acids, "may or may not be a true oncogene," Cho said. But it is clearly overexpressed in many tumor types, and that overexpression correlates with poor prognosis.
Several inhibitors of fatty acid synthase have shown preclinical antitumor activity. Of those, TVB-2640 is furthest along, though still early in clinical development. At the ASCO meeting, researchers at the University of Texas Health Science Center gave an update of a trial adding TVB-2640 to Avastin (bevacizumab, Roche Holding AG) in relapsed astrocytoma. Final data are expected later this year; for now, there have been neither alarming toxicities nor tantalizing hints of activity. A phase I trial in resectable colon cancer is also ongoing.