Targeting TIRR for Cancer Therapy: A Novel Target for Reactivating Lost p53 Suppressor Activity

A novel therapeutic strategy that may be widely applicable to multiple tumor types.

Therapeutics

Project Overview

While mutations and deletions of p53, one of the most common tumor suppressor genes in the human genome, are common, approximately 50% of cancers retain the ability to re-activate p53 function.
Inhibiting the Tudor-Interacting Repair Regulator (TIRR) protein can reactivate the tumor suppressor functions of p53 leading to cancer cell death.
Dana-Farber researchers have developed small molecule TIRR inhibitors that can reactivate p53 function in cancers that have at least one copy of normal p53 and are seeking an interested party for sponsored research or to license the technology for development to the clinic.

Technology

Due to its importance in preventing tumor growth, p53 reactivation remains a compelling strategy for cancer therapy.

Normal p53 function is lost in roughly 40% of all cancer patients. For decades, researchers have sought to uncover the various mechanisms that cancer cells use to block p53 activity with the therapeutic goal of restoring its tumor-suppressing function.

A team led by Dipanjan Chowdhury, PhD, David Scott, PhD, and Sirano Dhe-Paganon, PhD at Dana-Farber have identified and validated a new mechanism that cancer cells use to inhibit p53 function—over-expression of the Tudor-Interacting Repair Regulator (TIRR) protein.

Until recently, the primary pharmacological strategy to reactivate p53 in cancer has been through inhibition of MDM2, an enzyme that promotes degradation of many proteins, including p53. While there has been some success in clinical trials with various MDM2 inhibitors, their use has been limited by the severity of side effects that result from inhibition of a target that has many roles in cellular functions outside of regulating p53. Therefore, finding new targeted treatments that can specifically activate p53 without producing the side effects observed with the MDM2 inhibitors remains an active area of drug discovery and one with significant promise in treating many cancer types.

To this end, Dr. Chowdhury has identified the TIRR protein and has described how in cancer cells that retain wild-type 53, TIRR functions to inhibit p53 activity. In cells, p53 activity is regulated by a complex that forms between p53 and p53-binding protein 1 (53BP1). Dr. Chowdhury and colleagues have discovered that TIRR inhibits the formation of the 53BP1-p53 complex, resulting in reactivation of p53 leading to cancer cell death.

In addition, his group has shown that genetic deletion of the TIRR protein is lethal in cells that retain at least one copy of wild-type p53. With the addition of Dr. Scott and Dr. Dhe-Paganon, the team at Dana-Farber has embarked on a drug discovery program to develop small molecule TIRR inhibitors with the goal of restoring p53-mediated apoptosis without the limiting side effects seen with MDM2 inhibitors.

The Dana-Farber team has developed multiple assays to monitor TIRR and p53 function both biochemically and in cells. By using these novel assays, the team has identified chemical matter that interacts with and inhibits TIRR function. With the addition of structural data obtained by x-ray crystallography, the team has further developed multiple small molecules that can inhibit TIRR function and reactivate p53 in preclinical models of human cancer.

Further Details:

Chowdhury and Drané, et al. TIRR regulates 53BP1 by masking its histone methyl-lysine binding function. Nature, 2017, 543(7644):211-216
Chowdhury and Parnandi et al. TIRR inhibits the 53BP1-p53 complex to alter cell-fate programs, Mol. Cell, 2021, 1(12).

Team Members: Dipanjan Chowdhury, PhD, David Scott, PhD, Sirano Dhe-Paganon, PhD, Susan Kilgas, PhD, Maurício Tavares, PhD, Maurício Tavares, PhD, Hyuk-Soo Seo, PhD

Applications

TIRR inhibition is a novel therapeutic strategy that may be applicable to multiple tumor types that retain at least one copy of wild-type p53, representing approximately 50 percent of cancers, including breast cancer, renal cell carcinoma, prostate cancer, mesothelioma, GBM, and liver cancer. Rates of normal wild-type p53 are even higher in some cancers, such as clear cell renal cell carcinoma where more than 96 percent of tumors retain at least one copy of wild-type p53.

Opportunities

Dana-Farber welcomes discussions with interested parties to accelerate the development of the TIRR program to the clinic.

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