# Adipose tissue immunometabolism in ovarian cancer progression and chemoresistance

> **NIH NIH K00** · UNIVERSITY OF CHICAGO · 2024 · $95,636

## Abstract

Project Summary/Abstract
Ovarian cancer (OvCa) has an overall poor prognosis due in part to high rates of metastasis at the time of
diagnosis and few targeted therapeutic options. Microtubule targeted agents (MTAs), including the taxane
paclitaxel (PTX), are some of the most effective agents used for the treatment of women’s cancers, including
both breast and OvCas. Although PTX is often effective during the initial phase of treatment, the development
of resistance is a significant limitation to long-term anticancer efficacy. MTAs are collectively classified as
antimitotic agents; however, different drugs of this class have shown distinct effects on oncogenic signaling
pathways with notable differences demonstrated particularly between microtubule stabilizers, like PTX, and
microtubule destabilizers, such as the vinca alkaloids. Additionally, there is an opportunity to develop new
classes of MTAs that can circumvent well-established mechanisms of taxane resistance, including the
upregulation of drug efflux transporters. I hypothesize that the development of microtubule stabilizers that
circumvent clinically relevant mechanisms of taxane resistance, as well as the identification of biomarkers that
can be used to direct the more rational choice among different agents of this clinically validated and
mechanistically diverse class of drugs, will provide improved options for patients with taxane-resistant OvCa.
To complete my dissertation, I will use a combination of molecular and cellular biology, bioinformatics, and in
vitro and in vivo cancer pharmacology to identify key determinants for the targeted use of distinct MTAs for the
treatment of drug-resistant OvCa (F99 phase). I will test the hypothesis that the taccalonolide class of covalent
microtubule stabilizers will retain efficacy in locally disseminated, taxane-resistant OvCa models. Additionally, I
will follow up on findings that the Septin 9 isoform 1 (Sept9_i1) oncogene is differentially localized upon
treatment with microtubule stabilizers and destabilizers to test the hypothesis that Sept9_i1 can serve as a
biomarker for the differential response to these drugs, particularly in EGFR-driven breast and OvCas. In the
K00 phase, I will expand my training into the area of metabolic disorders to elucidate the molecular
mechanisms of adipocyte-mediated taxane resistance in OvCa. I will build on studies that demonstrate PTX
promotes IL-8 production in adipocytes due to its ability to directly activate the inflammatory TLR4 signaling
pathway and test the hypothesis that structurally distinct MTAs that do not activate TLR4 signaling will
circumvent this resistance mechanism both in vitro and in vivo, which could be used to inform on more rational
use of particular MTAs in subsets of women with OvCa. The proposed research will utilize an effective, but
mechanistically underappreciated, class of drugs to determine mechanisms underlying taxane resistance that
will guide future therapeutic choices. The...

## Key facts

- **NIH application ID:** 10853035
- **Project number:** 5K00CA264437-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Samantha Yee
- **Activity code:** K00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $95,636
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853035

## Citation

> US National Institutes of Health, RePORTER application 10853035, Adipose tissue immunometabolism in ovarian cancer progression and chemoresistance (5K00CA264437-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10853035. Licensed CC0.

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