Investigating PI3K signaling in metabolite-mediated immunosuppression in ovarian cancer
Active Project Grant Awarded Last action
- Award ID
- F30CA318410
- Recipient
-
Health Research, Inc. UEI YDWAYVVQHNK5
- Awarding agency
-
National Cancer Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $71,332
Award facts
- Assistance listing
- 93.398 Cancer Research Manpower
- Completion date 0% complete
- Originally
- Place of performance
- Buffalo, NY 14263, USA
Award details come from USAspending.gov.
Description
- Abstract
- High-grade serous ovarian cancer (HGSOC) is the leading subtype of ovarian cancer and accounts for the majority of disease-related mortality. These poor clinical outcomes are attributed to late-stage diagnosis, frequent recurrence, and limited therapeutic durability, reinforced by a markedly aberrant molecular landscape. Homologous recombination deficiency (HRD) has emerged as an important clinical biomarker, guiding the prediction of responsiveness to parp inhibitors and has significantly improved patient survival. Yet, nearly half of HGSOC cases are homologous repair proficient (HRP) and enriched for class I phosphoinositide 3-kinase (PI3KΑ) alterations, a group that fails to achieve meaningful therapeutic benefit, including to PI3KΑ inhibitors. This underscores the urgent need to better understand PI3KΑ-regulated oncogenic pathways to inform mechanism-based strategies for improving patient outcomes. To address this GAP in understanding, we developed a syngeneic PAM murine model of PI3KΑ-hyperactivated HGSOC, which conditionally expresses PIK3CAH1047R under a doxycycline(DOX)-inducible promoter, allowing temporal control of PI3KΑ activity for mechanistic interrogation of its role in HGSOC. Using this model, we have preliminary evidence that prolonged PI3KΑ inactivation is associated with intra-tumoral triglyceride (TG) alterations and an enriched immunosuppressive M2-like phenotype in the TME. These observations align with the hallmark features of the HGSOC TME, which is enriched in lipids and dominated by macrophage infiltration. Thus, we hypothesize that PI3KΑ-mediated regulation of TG metabolism promotes macrophage-mediated immunosuppression in HGSOC by establishing a lipid-enriched tumor microenvironment (TME) that favors M2-like TAM polarization. In aim 1, we will define how PI3KΑ pathway activity reprograms tumor lipid metabolism and drives macrophage-mediated immunosuppression in HGSOC. In aim 2, we will determine whether disrupting PI3KΑ-mediated lipid- macrophage crosstalk can reverse immunosuppressive remodeling of the TME in HGSOC. Overall, we employ a transformative preclinical platform to dissect the metabolic and immune consequences of PI3KΑ dysregulation, thereby identifying critical vulnerabilities that contribute to poor outcomes in HGSOC. By defining how PI3KΑ modulates triglyceride metabolism in tumor and TME, our study delivers mechanistic insights that are directly relevant to tumor progression and therapeutic resistance. Ultimately, these findings will advance the field by providing a biological foundation for therapeutic strategies that target both tumor cells and the TME, advancing the field toward precision medicine approaches that simultaneously reshape tumor and immune dynamics in PI3KΑ-hyperactivated HGSOC.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $35,666 | |
| Original award | $0 |
Quick answers
Who received award F30CA318410?
F30CA318410 was awarded to Health Research, Inc. by National Cancer Institute (National Institutes of Health) on January 31, 2027.
How much is award F30CA318410 worth?
$71,332 has been obligated on F30CA318410.
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