# Project 3: Inhibiting Oxidative Phosphorylation in Pancreatic Cancer

> **NIH NIH P50** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2020 · $402,801

## Abstract

PROJECT 3: Summary/Abstract 
Pancreatic ductal adenocarcinoma (PDAC) contributes to 6.9% of all cancer deaths in the US, and >1.5% of 
the US population will be diagnosed with PDAC in their lifetime. At present, the front-line therapy for advanced 
PDAC is multi-agent chemotherapy, most commonly, FOLFIRINOX or gemcitabine and nab-paclitaxel. Despite 
a better understanding of the genomic landscape and the importance of the tumor’s microenvironment, there 
has been no meaningful shift in the overall survival for this disease. An emerging concept is that mutations in 
KRAS and other canonical oncogenes that drive accelerated growth in PDAC and other tumors also directly 
reprogram cellular metabolism by augmenting nutrient acquisition, coupled to an increased flux through downstream metabolic pathways. Differential dependence on KRAS has also been linked with altered metabolic dependencies. The findings above indicate that the heterogeneity of PDAC is not only defined on the genomic 
and cellular levels, but also defined by distinctive metabolism programs controlled by oncogenic signaling. 
However, to date, the documented dependency of some tumors or tumor cell subpopulations on OXPHOS has 
not yet been exploited therapeutically. The University of Texas MD Anderson Cancer Center Institute for Applied Cancer Science (IACS) has developed IACS-010759, a potent inhibitor of complex I of the electron 
transport chain. The IACS compound has enabled expanded studies of OXPHOS inhibition in PDAC models 
that establish the preclinical rationale for evaluating IACS-010759 in patients in two contexts: (i) patients with 
treatment-naïve or refractory tumors that possess intrinsic sensitivity to OXPHOS inhibition, and (ii) in metabolically adapted disease following treatment with chemotherapy. The aims of this study are to explore the biology 
of response to treatment with IACS-010759 in these contexts, using a combination of ex vivo and in vivo studies, as well as evaluating patient response via clinical correlatives (transcriptomic signatures, hyperpolarized 
pyruvate-magnetic resonance imaging, quantitative CT scan) in planned phase 1b and phase 2a clinical studies in patients with treatment-naïve or refractory disease (phase 1b) or patients who have responded to prior 
standard-of-care chemotherapy (phase 2a). This research is significant because it will evaluate a completely 
novel targeted therapy approach for patients with PDAC in specific disease contexts that include (i) aggressive, 
mesenchymal-like tumors (“intrinsic” sensitivity) and metabolically adapted tumors post-treatment with chemo- 
toxic agents (“adaptive” sensitivity), the current standard of care for this patient population. The research is innovative because it will evaluate a completely novel targeted therapy approach for patients with PDAC in these 
specific disease contexts, and it employs innovative biophysical and metabolic imaging characterizations. It is 
anticipated that this res...

## Key facts

- **NIH application ID:** 9999487
- **Project number:** 5P50CA221707-02
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Shubham Pant
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,801
- **Award type:** 5
- **Project period:** 2019-08-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9999487

## Citation

> US National Institutes of Health, RePORTER application 9999487, Project 3: Inhibiting Oxidative Phosphorylation in Pancreatic Cancer (5P50CA221707-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9999487. Licensed CC0.

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