On April 17, 2023 Halda Therapeutics, a biotechnology company developing a novel class of cancer therapies called RIPTACTM (Regulated Induced Proximity TArgeting Chimeras) therapeutics, reported a poster presentation for its lead RIPTAC therapeutic program for prostate cancer at the annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper) being held in Orlando, Florida, from April 14-19, 2023 (Press release, Halda Therapeutics, APR 17, 2023, View Source [SID1234630213]). The preclinical data showed oral efficacy of the RIPTAC therapeutics as a monotherapy and demonstrated anti-tumor activity superior to the standard of care agent in prostate cancer, enzalutamide. Combination therapy with PARP inhibitors is also being explored and RIPTAC therapeutics may have a complementary mechanism.
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"Our presentation at AACR (Free AACR Whitepaper) is an exciting opportunity to share the growing body of evidence demonstrating the anti-tumor efficacy of the "hold and kill" mechanism of RIPTAC therapeutics which can be applied to address cancers in early or later-line therapy," said Kat Kayser-Bricker, PhD, Chief Scientific Officer of Halda Therapeutics. "These preclinical efficacy results of RIPTAC therapeutics targeting prostate cancer highlight the promise of a novel approach to overcome bypass mechanisms of resistance that evolve during cancer therapy, which is a common limitation of today’s precision oncology medicines."
The preclinical data describe the anti-tumor activity of prostate cancer RIPTAC therapeutics, novel orally bioavailable heterobifunctional small molecules, that use a unique "hold and kill" mechanism resulting in selective cancer cell killing by bringing together two proteins: the tumor-specific protein androgen receptor (AR) and an essential protein involved in transcription regulation. A trimeric complex is formed by the prostate cancer RIPTAC therapeutic and the two proteins which drives the formation of new protein-protein interactions; the resultant trimeric species thereby abrogates the function of the essential protein within AR-expressing prostate cancer cells, leading to selective cancer cell death.
The poster presentation, with lead author Xinheng Yu, PhD, Research Investigator at Halda, is entitled "Prostate Cancer RIPTACTM Therapeutics Demonstrate Activity in Preclinical Models of Enzalutamide-Resistant Prostate Cancer," and includes the following results:
In prostate cancer cells, the RIPTAC therapeutics demonstrated the formation of trimeric complexes with AR (and clinically relevant AR mutants) and a protein with essential function involved in transcription regulation.
In castrated mice bearing VCaP xenografts, multiple RIPTAC therapeutics demonstrated superior oral efficacy in vivo compared with enzalutamide, the current standard of care agent for prostate cancer.
RIPTAC therapeutics targeting prostate cancer downregulated genes involved in homologous recombination repair, inducing BRCAness. PARP inhibitors can induce synthetic lethality under these conditions, and combination therapy will be explored.
The design of the RIPTAC therapeutics targeting prostate cancer achieved desired anti-tumor activity and pharmacology through optimized trimeric complex formation, AR-selective cell killing, and oral bioavailability.
The poster presentation can be found on Halda’s website here.
About Prostate Cancer and mCRPC
Prostate cancer is the most common non-skin cancer in men. In the U.S., 1 in 8 men will be diagnosed with prostate cancer in his lifetime.1 Prostate cancer depends on the androgen receptor (AR), a transcription factor critical for prostate cancer growth and progression. Treatment initially relies on androgen deprivation therapy, as well as AR signaling inhibitors (ARSIs). However, resistance to antiandrogen interventions eventually emerges, and is driven by many heterogenous bypass mechanisms including genomic alterations in AR. The long-term prognosis for patients with metastatic castration resistant prostate cancer (mCRPC) is poor, with a relatively short overall survival. In the mCRPC form of the disease, more than 80% of patients harbor amplifications of the AR gene or the upstream enhancer region of DNA.2 AR remains expressed in tumors even if they are no longer AR dependent, dramatically reducing effectiveness of ARSIs, thus representing a vast unmet need.