Targeting Cancer’s Metabolic Vulnerability with IACS-10759, a Small Molecule Drug
Metabolic reprogramming is a key cancer hallmark, whereby cancer cells are able to evolve to depend on two distinct metabolic processes, glycolysis and oxidative phosphorylation, which help them survive – and thrive. We recently spoke to Phil Jones, Vice President for Therapeutics Discovery at The University of Texas MD Anderson Cancer Center, to learn more about the discovery and development of IACS-10759, identified as as a viable oxidative phosphorylation inhibitor. The potential of this small molecule drug is currently being explored as a treatment for acute myeloid leukemia (AML), solid tumors, and lung cancers harboring a specific epigenetic alteration.
Laura Mason (LM): Could you tell us more about the Therapeutics Discovery team at The University of Texas MD Anderson Cancer Center?
Phil Jones (PJ): Embedded within the University of Texas MD Anderson Cancer Center is the Therapeutics Discovery (TD) team – a unique group of more than 100 dedicated clinicians, researchers, drug developers and other scientific experts. Working together, our goal is to create new treatment options, develop small molecule drugs, biologics and cellular therapies, and bring these life-saving transformational medicines to patients quickly, safely and effectively. MD Anderson’s TD model aims to discover, develop and advance therapeutic candidates into clinical trials in specific patient populations quickly, demonstrating the distinct advantages of drug discovery at the bedside. This is conducted in collaboration with clinical researchers and basic scientists at MD Anderson in a seamless fashion. Working independently and in collaboration with industry, the TD team’s goal is to get from concept to clinic in 4 years or less – for example, our team identified and rapidly advanced IACS-10759 as a molecule for clinical development in just 18 months. TD has multiple collaborations with BioPharma in its quest to deliver innovative medicines, including partnerships with GSK, BI, Ipsen and Takeda, to name a few. Its process is not focused on commercial viability, but rather on tailoring therapies for use in patients being treated at MD Anderson where effective treatments do not exist today. The TD pipeline currently contains at least 20 diverse projects, focused across tumor types, and another three projects are expected to enter into clinical evaluation in the next 6 months.
LM: What is IACS-10759?
PJ: IACS-10759 is the first small molecule drug to be developed from concept to clinical trial by MD Anderson’s TD team. It is the product of a collaboration of the drug discovery team led by M. Emilia Di Francesco who engineered the drug, and the translational team headed by Joe Marszalek that identified the distinct patient populations that are expected to respond to inhibition of oxidative phosphorylation (OXPHOS). Most cancer cells rely on two metabolic processes, glycolysis and OXPHOS, to grow and survive. The mitochondria use oxygen to convert sugars, fatty acids and proteins into energy through OXPHOS. Cells also convert glucose to energy in the absence of oxygen through a less efficient process called glycolysis. Until recently, tumors were considered to depend exclusively on glycolysis for their survival; the development of this program clearly illustrates that a subset of tumors are critically dependent on OXPHOS for their metabolic and energetic needs. Based on our research, IACS-10759 is now being studied in two Phase 1 clinical trials, including for acute myeloid leukemia and solid tumor indications. As featured in Nature Medicine, we also are continuing to evaluate additional areas of development for this molecule, including for treating lung cancers harboring mutations in the SMARCA4 gene.
LM: Thinking about the pathway to the discovery of IACS-10759; What translation biology and medicinal chemistry approaches were used on route to the drug?
PJ: The discovery and development of IACS-10759 is the result of an effective collaboration of a cross functional team of around 50 scientists/researchers and clinicians including Joe and Emilia’s team, together with clinicians and translational researchers across around 15 MD Anderson departments. IACS-10759 was identified through an extensive medicinal chemistry campaign of lead optimization initially seeded with known modulators of HIF1α that act via inhibition of OXPHOS, and in total around 500-600 compounds were prepared and evaluated prior to the selection of IACS-10759 for clinical development. That specific molecule has all the right attributes for us to consider it the best compound to be used effectively in humans. In parallel, Joe’s team evaluated multiple clinical opportunities whereby the drug could be tested in humans before deciding on the specific clinical plans in distinct biomarker driven patient populations.
LM: Could you summarize preclinical findings presented in your recent paper and tell us about the ongoing Phase I trials investigating the potential of IACS-10759 for acute myeloid leukemia (AML) and solid tumors?
PJ: This research is at the forefront of an emerging hallmark of tumor biology – metabolic reprogramming. We know cancer cells evolve to rely on two key metabolic processes, glycolysis and oxidative phosphorylation (OXPHOS), to support their growth and survival. And while extensive efforts have focused on therapeutic targeting of glycolysis, our team found that OXPHOS has remained largely unexplored. The IACS-10759 team is focusing on a number of avenues to evaluate this pathway in the clinic. Our research showed that acute myeloid leukemia (AML) cells are highly dependent on the OXPHOS process. Likewise, we have identified that several tumors have genetic defects in glycolysis that make them critically dependent on OXPHOS. Furthermore, research across MD Anderson has shown that tumors develop resistance to several targeted therapies by upregulating OXPHOS for their survival. Therefore, we set out to develop a clinically viable inhibitor, applying our drug development expertise and capacity for rapidly testing and understanding the mechanism of possible drugs in preclinical models. Within 18 months, we identified IACS-10759 as a viable OXPHOS inhibitor, and then spent another 12 months to advance it through FDA mandated safety/toxicology studies. We are looking forward to the results of the Phase 1 studies in AML and solid tumors. To date, more than 25 subjects have been treated with IACS-10759, and we are seeing encouraging signs of biological activity in AML blasts, and the plasma concentration in plasma are approaching those required for activity in our preclinical models.
LM: Could you touch on the potential of IACS-10759 as a treatment for mutant lung cancers?
PJ: Clinically, there has been substantial success using targeted therapies against mutant EGFR and EML4-ALK fusion in lung cancer patients with the respective genetic alterations. However, most lung cancer patients do not harbor these genetic lesions and don’t benefit from these therapies. Thus, lung cancer remains a top cause of cancer mortality. Recent studies have shown that lung adenocarcinoma, a major sub-type of lung cancer, harbors frequent mutations in SWI/SNF complex, and SMARCA4 and ARID1A are the most frequently inactivated subunits. This occurs in around 10% of patients. While further investigation is needed, the data published in Nature Medicine showed that lung cancers with these gene mutations have enhanced oxygen consumption and increased respiratory capacity, making them susceptible to treatment with an OXPHOS inhibitor like IACS-10759.
LM: Could you expand on the “specific epigenetic alteration” mentioned in the recent press release?
PJ: Epigenetics is the study of changes in gene expression that do not involve changes in the underlying DNA sequence. In the nucleus, the DNA is tightly packaged and its transcription is controlled by a host of proteins, including the SWI/SNF complex that helps to unwind the DNA from its packaging. The SWI/SNF complex is a large multi-protein complex, and as described above, several members of this complex are frequently mutated in lung and other cancers, including SMARCA4 and ARID1A.
Phil Jones was speaking to Laura Elizabeth Mason, Science Writer for Technology Networks.