# Overcome the lineage plasticity conferred targeted therapy resistance in advanced prostate cancer

> **NIH NIH R00** · UT SOUTHWESTERN MEDICAL CENTER · 2020 · $249,000

## Abstract

PROJECT SUMMARY:
Despite the intensive effort and huge progress in cancer research, survival rate of many cancers remains low
and one of the biggest challenges is resistance to anti-cancer targeted therapies. Recently, a novel mechanism
of resistance has been recognized: by switching lineages from a cell type that is dependent on the drug target to
a different cell type that is not. My previous and ongoing work revealed that advanced prostate cancer might
escape antiandrogen therapy by increasing cellular lineage plasticity and transdifferentiate into a progenitor-like
transition state which no longer responds to treatment. I have further demonstrated that this lineage plasticity is
enabled by reactivation of SOX2, and can be reversed by inhibiting SOX2 expression. Although direct
therapeutic inhibition of SOX2 is currently infeasible, clinical interruption of SOX2 upregulation and its
downstream signaling is very promising, upon a clear elucidation of the mechanism of SOX2-driven plasticity.
Furthermore, my preliminary observation shows that epigenetic modification may contribute to this SOX2-driven
plasticity and resistance, which suggests novel therapeutic approaches targeting the epigenetic modifying
machinery. Building on these findings, the proposed studies in Aim 1 and 2 focus on elucidating the exact
mechanism of increasing plasticity and resistance driven by SOX2 in prostate cancer, possibly through
epigenetic modification, and developing novel strategies to prevent it. In an effort to identify additional genomic
alterations responsible for resistance, I successfully identified a novel tumor suppressor gene, SYNCRIP, that
confer resistance to antiandrogen therapy via in vivo library screening. Because of the known interaction between
SYNCRIP and deaminase Apobec-1, I will also test the hypothesis that loss of SYNCRIP in prostate cancer
may confer resistance by releasing the inhibition of Apobec-1-driven methylation/demethylation, thus leading to
increased epigenetic reprogramming and cell plasticity in Aim 3. The potential outcome of proposed studies will
provide novel insight into the connection between epigenetic modification and resistance to targeted therapy in
advanced prostate cancer, as well as novel approaches for clinical intervention of resistance. The support of the
K99/R00 award for these proposed studies will provide me the protected time and required training in the fields
of cancer epigenetics, chromatin biology and bioinformatics, as well as serve as a platform for me to obtain
career development trainings such as grant writing, job application, manuscript writing and lab management. I
believe all these supports and trainings are critical for achieving my career goal to become an independent
investigator studying targeted therapy resistance.

## Key facts

- **NIH application ID:** 9893832
- **Project number:** 5R00CA218885-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Ping Mu
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-04-15 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893832

## Citation

> US National Institutes of Health, RePORTER application 9893832, Overcome the lineage plasticity conferred targeted therapy resistance in advanced prostate cancer (5R00CA218885-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9893832. Licensed CC0.

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