A breakthrough approach in cancer metabolism research that targets oxidative phosphorylation in aggressive tumors
Imagine if we could fight cancer not by indiscriminately poisoning rapidly dividing cells, as traditional chemotherapy does, but by cutting off the unique energy supply that feeds aggressive tumors.
Focuses on cancer's metabolic vulnerabilities
25+ scientists across multiple specialties
First small molecule drug from MD Anderson's Therapeutics Discovery team
At the forefront of this revolution stands IACS-10759, an experimental drug that represents a completely different approach to cancer treatment. This compound specifically targets a metabolic vulnerability in some of the most challenging cancers, including certain types of acute myeloid leukemia, brain tumors, and triple-negative breast cancer .
Highly efficient energy production in mitochondria that requires oxygen and extracts maximum energy from nutrients.
Less efficient process that doesn't require oxygen, known as the Warburg effect in cancer cells 6 .
Recent research has revealed that many aggressive and treatment-resistant cancers actually rely heavily on OXPHOS to fuel their growth and survival 7 8 , creating a crucial metabolic vulnerability that can be targeted therapeutically.
Developed at The University of Texas MD Anderson Cancer Center through their Therapeutics Discovery team .
Specifically binds to the ND1 subunit at the entrance to the quinone binding channel in mitochondrial complex I 2 .
Disrupts electron transport chain and depletes aspartate, creating energy blackout and metabolic collapse 3 .
Disrupts the electron transport chain, immediately cutting off the cell's primary ATP production and creating an energy blackout within the cancer cell.
Simultaneously depletes aspartate, a crucial building block for nucleotides, starving the cell of essential materials for replication 3 .
Patients: 17 with relapsed/refractory acute myeloid leukemia
Prior Therapies: Median of 3-4 prior treatments
Dosing: Twice-daily regimen
Patients: 23 with advanced solid tumors
Prior Therapies: Median of 3-4 prior treatments
Dosing: Once-daily and twice-daily regimens
| Adverse Event | AML Trial (n=17) | Solid Tumor Trial (n=23) |
|---|---|---|
| Elevated blood lactate | 35% (grade 1-2) 53% (grade ≥3) |
83% (grade 1-2) 9% (grade ≥3) |
| Peripheral neuropathy | 12% (grade 1-2) 6% (grade ≥3) |
35% (grade 1-2) 4% (grade ≥3) |
| Nausea | 29% (mostly grade 1-2) | 65% (mostly grade 1-2) |
| Vomiting | 18% (mostly grade 1-2) | 30% (mostly grade 1-2) |
Data adapted from trial results published in Nature Medicine 2
The neurotoxicity and high lactate levels prevented patients from maintaining drug exposures sufficient to kill cancer cells, creating a narrow therapeutic window 2 .
| Research Tool | Function/Application | Example from IACS-010759 Research |
|---|---|---|
| HRE-eGFP-ODD Reporter System | Dynamic monitoring of hypoxia in live cells | Used in spheroid models to quantify hypoxia reduction by OXPHOS inhibitors 4 |
| Patient-Derived Xenografts (PDXs) | Testing drug efficacy in human tumors grown in mice | Identified TNBC subtypes most sensitive to IACS-010759 8 |
| Triphenylphosphonium (TPP+) Conjugation | Mitochondria-targeting moiety to improve drug specificity | Enhanced tumor uptake of atovaquone compared to healthy cells 1 4 |
| Seahorse Analyzer | Real-time measurement of oxygen consumption rate (OCR) | Confirmed reduced OCR following IACS-010759 treatment 3 |
| shRNA Library Screens | Identify synthetic lethal partners for combination therapies | Discovered CDK4 inhibition as potential combination strategy 8 |
Pairing OXPHOS inhibitors with CDK4/6 inhibitors or multikinase inhibitors for enhanced efficacy 8 .
Synergistic ApproachIdentifying patients with high mitochondrial gene expression or specific genetic alterations 8 .
Personalized MedicineThe potential to alleviate tumor hypoxia—a key cause of radiation therapy resistance—represents another promising application for OXPHOS inhibitors 1 4 . By reducing oxygen consumption in tumor cells, these drugs may effectively "normalize" the tumor microenvironment and improve the efficacy of both radiotherapy and immunotherapy.
The story of IACS-010759 illustrates both the tremendous challenges and exciting possibilities of targeting cancer metabolism. While the initial clinical results highlighted the difficulties of balancing efficacy and toxicity, the research journey has fundamentally advanced our understanding of how cancer cells fuel their growth—and how we might strategically cut off their energy supply.
The legacy of IACS-010759 extends far beyond the compound itself. The research it sparked continues to drive innovation in mitochondria-targeted therapies, rational combination strategies, and biomarker development—all critical elements in the evolving landscape of precision oncology.