Foxp3Δ3 As A Biomarker For Treatment Response And Novel Target For Anti-Cancer Therapy
Tech ID: 29753 / UC Case 2015-686-0
Chin group at UCLA has discovered that an isoform of the protein Foxp3 is a
robust biomarker of bladder cancer sensitivity to chemotherapy, including
cisplatin- and gemcitabine-based treatments.
carcinoma of the bladder comprises the majority of bladder cancer cases and
represents the 9th leading cause of cancer mortality in the world. Resistance
to chemotherapy is a major clinical problem; In patients with advanced bladder
cancer, 50 to 60% do not respond to systemic cisplatin-based chemotherapy,
which is the standard of care. A biomarker that can predict treatment response
would assist physicians in treatment decisions and greatly benefit patients.
Arnold I. Chin from UCLA has found that Foxp3Δ3, an isoform of a transcription
factor Foxp3, is preferentially expressed in bladder cancer cell lines and
primary tumors. His research has demonstrated that Foxp3Δ3 overexpression confers
resistance to cisplatin and gemcitabine. Therefore, determining levels of this
isoform can be used as a prognostic indicator and guide treatment for bladder
- Specifically, the
inventor found that knockdown of Foxp3Δ3 sensitized
bladder cancer cells to both cisplatin and gemcitabine. Therefore, Foxp3Δ3 can
serve as a diagnostic biomarker for cisplatin and gemcitabine sensitivity in
bladder cancer patients.
- Dr. Chin also found
that Foxp3Δ3 expression is also correlated to sensitivity to HDAC inhibitors,
and that Foxp3Δ3 expression levels may be used as a prognostic biomarker for
this therapy as well.
patient response to chemotherapies, such as cisplatin, gemcitabine, and HDAC
physicians in making treatment decisions
monitor patient response to therapy during treatment from urine and/or blood
- This biomarker may also
be used as a prognostic and/or diagnostic biomarker for other cancers including
but not limited to lung, ovarian, cervical, lymphomas, germ cell cancers
- Physicians can serially monitor Foxp3Δ3 levels in patients during treatment by testing urine and/or blood.
Differential expression of Foxp3Δ3 over Foxp3 in bladder cancer patients is high
- There is an 8- to 40-fold increase in expression of the Foxp3Δ3 isoform compared to full-length Foxp3 in bladder cancer.
State Of Development
and Foxp3Δ3 expression has been analyzed in a tumor tissue microarray, as well
as human clinical specimens. Dr. Chin has further characterized the role of
Foxp3 and Foxp3Δ3 in both in vitro and
in vivo model systems.
- Higher stage primary
tumors had a higher expression of Foxp3, preferentially expressing the Foxp3Δ3
- Stable SW780 cell lines
expressing Foxp3Δ3 demonstrated enhanced sphere formation and expression of
stem cell markers in vitro, and
larger tumors with more luminal differentiation in vivo xenografts
- Foxp3Δ3 is the
predominant isoform in multiple primary bladder tumors, as well as cancer cell
of Foxp3Δ3 to Foxp3 ranged from 8:1 to 42:1)
- The researchers
demonstrated that while Foxp3Δ3 overexpression induced resistance to cisplatin
and gemcitabine, it also surprisingly sensitized cytotoxicity to HDAC
- Conversely, knockdown
of Foxp3 by approximately 40% showed that decreasing Foxp3 expression
sensitized bladder cancer cell lines to cisplatin and induced HDAC inhibitor
- Zhang H, Prado K, Zhang KX, E. M. Peek, J. Lee, X. Wang, J. Huang, G. Li, M. Pellegrini, A. I. Chin, Biased Expression of the FOXP3D3 Isoform in Aggressive Bladder Cancer Mediates Differentiation and Cisplatin Chemotherapy Resistance, Clin. Cancer Res., 2016.