# SPROUTY: PUTATIVE ONCOGENE IN COLORECTAL CANCER

> **NIH VA I01** · HARRY S. TRUMAN MEMORIAL VA HOSPITAL · 2020 · —

## Abstract

Colorectal cancer (CRC) is the leading cause of cancer-related death in the United States.
Cancer death in CRC is mainly due to tumor recurrence and distant metastasis. Sprouty2
(SPRY2), an endogenous suppressor of receptor tyrosine kinase (RTK)/ Mitogen Activated
Protein Kinase (MAPK) signaling pathways, acts as a tumor suppressor in breast, prostate, and
liver cancer. We discovered oncogenic role of SPRY2 in CRC. The objectives of this application
are to assess the requirement and significance of SPRY2 in CRC progression, treatment and
recurrence.
Studies demonstrated that upregulation of SPRY2 accentuates cancer phenotype whereas
suppression of SPRY2 augments epithelial features and decreases epithelial mesenchymal
transition (EMT). We hypothesize that deletion of SPRY2 will suppress CRC. To test this
hypothesis, in AIM 1, SPRY2 LoxP/Vil-Cre ERT2 mouse model will be utilized. Effect of SPRY2
deletion on azoxymethane (AOM)-induced colonic tumorigenesis will be studied. It was further
established that SPRY2 stable transfection significantly increased RTK cMet expression.
Suppression of SPRY2 decreased endogenous and TGF- induced cMet protein and mRNA
expression. In AIM 2, we will delineate TGF-/SPRY2 dependent transcriptional regulation of
cMET in colon cancer cell lines. While inhibitors of epidermal growth factor receptor (EGFR) are
beneficial in the treatment of metastatic CRC, increases in cMet expression and EMT are
resistance mechanism to anti-EGFR therapy. In AIM 3, effect of SPRY2 suppression on tumor
growth (xenograft model) and metastasis (cecal implantation model) of gefitinib and cetuximab-
resistant colon cancer cell lines will be investigated. We hypothesize that SPRY2 suppression will
sensitize gefitinib and cetuximab-resistant colon cancer cells to anti-EGFR therapy. Studies will
be extended to analyze effect of SPRY2 deletion during gefitinib treatment in vivo SPRY2
LoxP/Vil-Cre ERT2 mouse model. Significance of SPRY2 with tumor recurrence and long-term
survival is not clear. In AIM 4, we hypothesize that SPRY2 expression in primary tumors may
correlate directly with tumor recurrence and long-term survival. Further, as SPRY2 is the key
regulator of Ras-dependent pathways, we have extended our investigations to assess the
association of SPRY2 expression with Ras mutations [KRAS (codon 12, 13) and NRAS (codon
12, 13)] in recurrence. Implication of concomitance of SPRY2 expression and Ras mutations in
primary tumors to disease outcome will be investigated. For this analysis sporadic stage II-III
archived formalin-fixed paraffin embedded tumors (FFPET) that are linked to outcomes at 5 years
will be utilized.
To our knowledge, this is the first study to demonstrate a cancer promoting role of SPRY2 in
CRC. We have established hypotheses based on our preliminary data and publications. The
proposed study is a multi-pronged approach to assess the effect of SPRY2 deletion on tumor
growth, examine the role of SPRY2 in acquired resistance...

## Key facts

- **NIH application ID:** 9861186
- **Project number:** 5I01BX000824-08
- **Recipient organization:** HARRY S. TRUMAN MEMORIAL VA HOSPITAL
- **Principal Investigator:** SHARAD KHARE
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-10-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9861186

## Citation

> US National Institutes of Health, RePORTER application 9861186, SPROUTY: PUTATIVE ONCOGENE IN COLORECTAL CANCER (5I01BX000824-08). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9861186. Licensed CC0.

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