# Vascular image-guided optimization of response (VIGOR) to therapy in kidney cancer

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $466,346

## Abstract

We will develop the application of a promising novel vascular disrupting agent (VDA) in combination with
leading therapies to enhance treatment of kidney cancer. Renal cell carcinoma (RCC) is usually characterized
by inactivation of the von Hippel Lindau (vHL) tumor suppressor protein, promoting accumulation of Hypoxia
Inducible Factor (HIF) and consequent development of extensive vasculature. The endothelium of normal
blood vessels is largely quiescent, but the invasive neovasculature of tumors is immature, lacks pericyte
support, and exhibits increased permeability providing a selective target for cancer therapy. The therapeutic
goal of VDAs is to cause rapid widespread disruption of established tumor vasculature leading to regional
ischemia, induction of hypoxia and tumor necrosis. We have identified OXi8007 as a new potent, water-soluble
VDA prodrug generating protracted vascular disruption, dose dependent tumor growth delay and no apparent
systemic toxicity. However, VDA monotherapy generally results in re-growth at the tumor periphery and
OXi8007 will likely be most effective in augmenting current lead therapies based on complementary modes of
action. We will investigate a small-molecule HIF-2 antagonist, PT2977 developed by Peloton Therapeutics,
which represents a new class of chemotherapeutic in early clinical trials. Meanwhile, cabozantinib, the small-
molecule kinase inhibitor that targets the c-MET receptor, AXL, and VEGFR-2 was recently approved as a first
line treatment option for patients with metastatic RCC. We also recognize the emerging success of
immunotherapy and anticipate that OXi8007-induced necrosis will enhance antigen presentation promoting
response. Our overarching hypothesis is that combining these therapeutic approaches will achieve robust long
term control of RCC.
Investigations will benefit from the resources of the UT Southwestern Kidney Cancer SPORE, which has
developed a number of new patient derived tumor lines exhibiting differential sensitivity to HIF-2 antagonists.
Effective therapy combination will likely depend on timing of administration of the respective agents and non-
invasive imaging will reveal the spatial and temporal pharmacodynamics of tumor response. Bioluminescence
imaging (BLI) will effectively interrogate luciferase-transfected RENCA cells in immunocompetent mice. In
addition, recently available multispectral optoacoustic tomography (MSOT) non-invasively reveals vascular
extent and regional oxygenation without the need for exogenous reporter molecules or cell transfection.
Complementary cell-based studies are designed to further explore OXi8007 mechanism of action. Effectively
combining targeted therapies should enhance treatment and ultimately survivorship of kidney cancer patients.
The goal of these investigations is to demonstrate effective combination therapy as a foundation for
investigations in large animals and translation to the clinic.

## Key facts

- **NIH application ID:** 10442463
- **Project number:** 5R01CA244579-03
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** RALPH P. MASON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $466,346
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10442463

## Citation

> US National Institutes of Health, RePORTER application 10442463, Vascular image-guided optimization of response (VIGOR) to therapy in kidney cancer (5R01CA244579-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10442463. Licensed CC0.

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