Researchers at The University of Texas MD Anderson Cancer Center in Houston are developing an inhibitor of oxidative phosphorylation, IACS-10759, that targets complex I of the mitochondrial electron transport chain. Ongoing early clinical studies indicate that IACS-10759 appears safe, tolerable, and active; the drug has also shown efficacy in mouse models of ibrutinib-resistant mantle cell lymphoma.

Interest in therapeutically targeting cancer metabolism has largely focused on glycolysis over the years, but of late the dependence of some tumors on mitochondrial oxidative phosphorylation (OXPHOS) has emerged as another vulnerability worth exploiting. Researchers at The University of Texas MD Anderson Cancer Center (MDACC) in Houston have been studying the idea and described clinical results of their investigational OXPHOS inhibitor, IACS-010759, at the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, IL, May 31–June 4.

“We identified a lead compound from extensive medicinal chemistry efforts, then built in the properties to what is now IACS-010759,” says Joseph Marszalek, PhD, who co-leads TRACTION, a translational research platform. He is spearheading this drug's development in collaboration with Emilia Di Francesco, PhD, and Philip Jones, PhD, of the Institute for Applied Cancer Science (IACS). Both TRACTION and IACS are part of MDACC's Therapeutics Discovery division, which aims to speedily advance bench findings into clinical trials.

IACS-010759 selectively inhibits complex I of the mitochondrial electron transport chain (ETC), thereby disrupting OXPHOS, the metabolic process some tumor cells rely on for growth and survival. “The rationale is that this heavy dependence—in contrast with normal cells being able to utilize backup pathways—will result in a sufficient therapeutic window for antitumor activity,” explains Timothy Yap, MD, PhD, who is leading a phase I trial evaluating IACS-010759 in solid tumors.

At ASCO, Yap presented early findings from this study: To date, 21 patients with various cancers, including colorectal, prostate, and pancreatic, have received IACS-010759, first in an induction phase of once-daily dosing for 1 week, followed by a twice-weekly maintenance phase. “We've seen mild increases in lactate levels in most patients, which we take as preliminary evidence that we're hitting our target,” Yap says. The drug appears safe and tolerable, with no metabolic acidosis observed and low-grade nausea, fatigue, myalgia, and neuropathy among the main side effects.

So far, one patient whose metastatic castration-resistant prostate cancer was refractory to multiple prior therapies has had a confirmed partial response, and another eight have seen their disease stabilize. “I'd say this is indeed an active drug,” Yap remarks. “The question now is getting the right dose that will be well tolerated in the long run.”

Chi Van Dang, MD, PhD, scientific director of the global Ludwig Institute for Cancer Research, notes that the idea of targeting complex I came about after researchers observed that the type II diabetes drug metformin was associated with reduced cancer risk in large epidemiology studies. “Metformin turned out to be an inhibitor of complex I, albeit a rather weak one,” Dang says. “So, there was precedent that you could get away with blocking this particular component of the ETC.”

With IACS-010759, “the data so far seem to indicate that complex I inhibition—in a stronger way [than metformin]—can be done safely, which is pretty exciting,” adds Matthew Vander Heiden, PhD, of the Massachusetts Institute of Technology in Cambridge. Both he and Dang laud the MDACC researchers for forging into a therapeutic area that, its potential notwithstanding, “has turned out far more complex than we thought,” Dang remarks.

One reason the cancer metabolism field has been slow to make therapeutic strides is that “no one really knows who should receive these drugs,” Vander Heiden observes. IACS-010759, though, is geared toward addressing unmet needs in specific patient populations, and another MDACC group led by Michael Wang, MD, hopes their recent findings will help determine who might benefit from this drug, at least in mantle cell lymphoma (MCL).

Wang and his team were probing the development of resistance to the Bruton tyrosine kinase inhibitor ibrutinib (Imbruvica; Janssen), which predicts poor survival, among patients with MCL. “We found that this resistance is mediated by metabolic reprogramming on the part of tumor cells—but not toward glycolysis,” he explains. “In fact, the Warburg effect is completely not the case here; resistant MCL cells are instead rewired to rely on OXPHOS.”

Besides comprehensive genomic analyses of ibrutinib-treated patient samples, “we did a series of metabolic assays and functionally proved the OXPHOS dependency of resistant cells,” adds Krystle Nomie, PhD, a study co-author. Then, by way of a collaborative relationship with Therapeutics Discovery, “we learned that we had a drug available to test our findings.” The team reported that IACS-010759 markedly suppressed tumor growth and improved survival in ibrutinib-resistant mouse models of MCL derived from patient xenografts.

Wang and his colleagues also pinpointed a 63-gene signature that distinguishes ibrutinib resistance from sensitivity in MCL. Many of these genes—upregulated in resistant tumors—are related to metabolism, he says, including the mitochondrial transporter SLC25A19. This signature has been validated in an independent cohort of patients with MCL and is now patented, Nomie says. “We'll use it predictively—the idea would be to biopsy patients and, if the resistant signature shows, treat them with an OXPHOS inhibitor instead of ibrutinib.”

Other preclinical findings from MDACC have suggested that loss of ENO1 or mutations in SMARCA4 could be predictive biomarkers of sensitivity to OXPHOS inhibition. ENO1 loss leads to glycolysis deficiency in cholangiocarcinoma, glioblastoma, and liver cancer cells; SMARCA4 mutations, found in lung adenocarcinoma, increase cells' oxygen consumption. Both result in high dependence on OXPHOS, so Yap and his co-investigators plan to include expansion cohorts targeting these aberrations in their trial. As well, a cohort for patients with ibrutinib-resistant MCL is in the works.

For biomarker discovery, “perhaps a better question to ask is not why one tumor type cares more than another about OXPHOS as a whole, but about complex I in particular,” Vander Heiden points out. “Getting to the heart of this differential dependence on specific components of the ETC could help shed light, down the road, on who best to receive a drug like IACS-010759.” Meanwhile, he hopes the early clinical data from MDACC continue to hold up, so “we move the needle, even a bit, for targeting cancer metabolism.”

IACS-010759 is currently being evaluated in one other phase I trial for relapsed/refractory acute myeloid leukemia. Combination studies will be considered in due course, Marszalek says, “to see if adding our agent to standard-of-care therapies such as ibrutinib prevents relapse and improves progression-free survival.”

Ideally, the researchers would show clinical activity with IACS-010759 and then find an industry partner to advance its development, Marszalek adds. “But if this turns out to be a niche population that may not interest pharma as much, yet we do see robust responses, we could entertain the idea of developing this drug ourselves. After all, our stakeholders aren't shareholders—they're patients.” –Alissa Poh

An immune angle

When it comes to targeting metabolic vulnerabilities in cancer, how such drugs may influence the tumor microenvironment—particularly immune cells nearby—also merits further research, says Chi Van Dang, MD, PhD, of the global Ludwig Institute for Cancer Research.

For instance, “we know that cytotoxic T cells and [antitumor] M1 macrophages rely on glycolysis,” Dang says. “So, if you have a good drug that hits this process in cancer cells, might you also inadvertently tip the balance toward compromising the immune system? It's a real conceptual issue.”

On the other hand, immunosuppressive M2 macrophages and other protumor cell types, including regulatory T cells and myeloid-derived suppressor cells, depend on various mitochondrial functions, including oxidative phosphorylation (OXPHOS). Recently, researchers at The University of Texas MD Anderson Cancer Center in Houston reported that brain metastases from patients with melanoma displayed considerable immunosuppression and increased expression of genes related to OXPHOS. The investigational OXPHOS inhibitor IACS-010759, which targets complex I of the electron transport chain, blocked formation of such metastases in mouse models, improving survival.

Generally, then, “the promising aspects of going after complex I include not only direct tumor effects, but possibly eradicating unwanted immune cells that are helping the tumor thrive,” Dang says. He serves on the scientific advisory board of Cranbury, NJ–based Rafael Pharmaceuticals (formerly Cornerstone), whose pipeline includes devimistat (CPI-613), designed to target key enzymes of the tricarboxylic acid cycle, which precedes OXPHOS. Clinical assessments of devimistat include an ongoing phase III trial, with or without standard FOLFIRINOX, in metastatic pancreatic cancer; during phase I, several complete remissions were seen—an “unheard of” achievement given the tumor type, Dang notes.

“The only rationale I have,” he says, “is the added bonus of enhanced antitumor immune effects, not just cancer cells being killed” with devimistat. Given this possibility with drugs that target mitochondrial functions, “I wouldn't be too restrictive in clinical studies of IACS-010759, in terms of finding hard biomarkers to use,” Dang remarks. “It might be worth seeing if adding this drug induces responses in tumors that have been refractory to, say, immune checkpoint inhibition alone.” –AP