# Dissecting Skp2 functions in pRb and p53 doubly deficient tumorigenesis

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $382,013

## Abstract

Abstract
Cancer therapies targeting a specific signaling pathway (targeted therapy) in a specific tumor (personalized
therapy) are the current “state-of-the-art”, while treatment and management for advanced cancer remain the
barrier to overall cancer treatment success. One common feature of advanced cancer is frequent genetic
inactivation of pRb and p53, the two major tumor suppressors. Finding effective treatments for these cancers
depends on finding antitumor mechanisms that remain effective when both pRb and p53 are genetically
inactivated. We have succeeded in blocking pRb and p53 doubly deficient tumorigenesis in mouse tumor
models by deleting Skp2. We now propose to use pRb and p53 doubly deficient prostate tumorigenesis in
mice to model metastatic castration resistant prostate cancer (mCRPC) in patients to identify new treatment for
this lethal cancer. The advance in TCGA of prostate cancer has documented statistically significant co-
occurrences of RB1 and TP53 in mCRPC, providing the rationale for our proposed studies. The emerging
cancer organoids system has established a resource of six mCRPC organoid lines and we have established
mouse prostate tumor organoids to translate our mouse model findings to human mCRPC side-by-side on the
organoid platform. In this application, we propose to determine the potential of targeting the Skp2/Cks1 pocket
to inhibit mouse DKO prostate tumorigenesis and translate the findings to human mCRPC on organoid
platform followed by metastasis assay with organoid cells in immune compromised mice (Specific Aim 1), and
to determine mechanism and role of Skp2 function in promoting Warburg effects in DKO prostate
tumorigenesis and determine the effects of inhibiting LDHA and Skp2/Cks1 pocket in combination in mouse
DKO prostate tumorigenesis and translate the finding to human mCRPC in organoids and in metastasis assays
(Specific Aim 2).

## Key facts

- **NIH application ID:** 10023167
- **Project number:** 5R01CA201458-06
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** EDWARD L SCHWARTZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $382,013
- **Award type:** 5
- **Project period:** 2016-06-03 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10023167

## Citation

> US National Institutes of Health, RePORTER application 10023167, Dissecting Skp2 functions in pRb and p53 doubly deficient tumorigenesis (5R01CA201458-06). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10023167. Licensed CC0.

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