▎ WuXi AppTec content team editor
PARP inhibitors are targeted therapies developed by using dna damage response (DDR) defects in tumors, which target tumor cells while avoiding harm to healthy cells, and have been approved by regulatory agencies to treat cancer types such as breast cancer, ovarian cancer, and prostate cancer that carry DDR defects. After the success of PARP inhibitors, researchers are also developing a new generation of targeted therapies for DNA damage responses. In this article, WuXi AppTec's content team will share with readers the latest advances in next-generation targeted therapies that target DNA damage responses at the AACR conference.
The results of the first human clinical trial of AstraZeneca PARP1 inhibitors are published
AstraZeneca's AZD5305 is a highly specific next-generation PARP1 inhibitor and trapper. Preclinical studies have shown that it has better tolerability compared with the first-generation PARP1/2 inhibitors, as well as binding to the target and efficacy.
In the first human clinical trial, the researchers treated 61 patients with advanced breast, ovarian, prostate or pancreatic cancer with AZD5305 who carried BRCA1/2, PALB2 or RAD51C/D mutations.
Of the 40 patients who could assess efficacy, 10 achieved partial remission and 11 were disease stable. It is worth mentioning that the clinical benefit is not related to whether or not you have previously received PARP inhibitor treatment. Of the 13 patients who underwent circulating tumor DNA (ctDNA) testing, ctDNA levels decreased in 8 patients, including all prostate cancer patients carrying BRCA2 mutations.
Image credit: 123RF
Bayer ATR inhibitors show positive clinical activity
ATR is an important member of the DNA damage response signaling network, which is activated by DNA damage or replication stress. By blocking ATR-mediated signaling pathways, ATR inhibitors block the activation of DNA damage checkpoints, disrupt DNA damage repair, and inhibit tumor cell growth.
Elimusertib, developed by Bayer, is a highly selective and powerful ATR inhibitor. The Phase 1b Extended Clinical Study published by AACR showed that among 143 patients with advanced solid tumors with different DDR deficiencies, elimusertib kept the disease under control for about 35% of patients for at least 16 weeks. Among patients with ovarian cancer, 27.8% had a clinical benefit of more than 6 months, including those who were resistant to platinum-containing chemotherapy and had been treated with PARP inhibitors. In patients with attenuated ATM expression, the partial response rate was 8.9%, and in 55.9% of patients, the disease was stable.
The researchers say more research is needed to discover biomarkers that predict which patients will be most likely to benefit from elimusertib monotherapy.
Image credit: 123RF
In the treatment of PARP inhibitor-resistant ovarian cancer, ATR inhibitors achieve an overall response rate of 25%.
Repare Therapeutics also presented the results of a Phase 1/2 clinical trial of the oral ATR inhibitor RP-3500 at the AARR conference. The results of the trial showed that RP-3500 showed particularly promising activity in the cohort of advanced ovarian cancer (n=20). 90% of these patients developed resistance after previous treatment with PARP inhibitors, and 85% were resistant to platinum-containing chemotherapy. The overall response rate of RP-3500 in this patient population was 25%, including 1 complete response and 3 partial responses. Median progression-free survival was 35 weeks.
Clinical trial results of RP-3500 (Image source: Repare Therapeutics official website)
RP-3500 also exhibited anti-cancer activity in patients with other types of cancer, with a disease control rate of 43% for all patients, including complete remission, partial remission, and disease stabilization.
In the treatment of platinum-containing chemotherapy-resistant ovarian cancer, the objective response rate of Wee1 inhibitors was 30.2%
Wee1 is an important target for the new generation of DDR targeted therapies, a protein kinase that plays a key role in regulating cell cycle progression. It can prevent cells carrying DNA damage from entering mitosis. By inhibiting Wee1, Wee1 inhibitors can allow cells carrying DNA damage to enter mitosis without repairing the damage, leading to dna damage accumulation and cell death.
▲Wee1 is a clinically validated target targeting DDR (Image source: Zentalis official website)
Zentalis presented the results of a Phase 1b clinical trial in which its Wee1 inhibitor ZN-c3 was combined with chemotherapy to treat patients resistant to platinum-containing chemotherapy or refractory ovarian cancer. The trial results showed that in 43 patients who could assess efficacy, the combination therapy achieved an objective response rate of 30.2% and a disease control rate of 86.0%.
▲ Clinical trial results of ZN-c3 (Source: Zentalis official website)
Ai-aided drug development, Schr dinger publishes latest research on Wee1 inhibitors
Schr dinger is a biotechnology company that uses a physics-based software platform to revolutionize the discovery and development of new drugs. The company presented preclinical data from its Wee1 inhibitor R&D program at the AACR conference.
As mentioned above, Wee1 is an important target for targeting DDR, and several Wee1 inhibitors have entered the clinical development phase. The key to improving Wee1 inhibitors is to improve the specificity of the inhibitor (reducing the toxic side effects of off-target effects) and to reduce the inhibition of CYP3A4. CYP3A4 plays an important role in drug metabolism, and reducing inhibition of CYP3A4 may increase the likelihood of Wee1 inhibitors being used in combination with other drugs.
Schr dinger's research showed that the company's Wee1 inhibitors are highly kinase-selective and do not produce time-dependent inhibitory effects on CYP3A4. It has the potential to treat cancer as part of monotherapy or combination therapy.
▲Schr dinger's Wee1 inhibitor has optimized selectivity and physicochemical characteristics (Source: Schr dinger official website)
It is expected that the new generation of therapies that target DDR deficiencies can provide patients with more and better treatment options.
Resources:
[1] Repare Therapeutics Presents Updated Clinical Data from the Ongoing Phase 1/2 TRESR Study of RP-3500 Monotherapy in Solid Tumors at the 2022 AACR Annual Meeting. Retrieved April 12, 2022, from https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-presents-updated-clinical-data-ongoing-phase
[2] Schr dinger Reports New Preclinical Data Supporting Advancement of Its Wee1 Inhibitor Program at American Association of Cancer Research 2022 Annual Meeting. Retrieved April 12, 2022, from https://ir.schrodinger.com/news-releases/news-release-details/schrodinger-reports-new-preclinical-data-supporting-advancement
[3] Phase Ib expansion trial of the safety and efficacy of the oral ataxia telangiectasia and Rad3-related (ATR) inhibitor elimusertib in advanced solid tumors with DNA damage response (DDR) defects. Retrieved April 12, 2022, from https://www.abstractsonline.com/pp8/#!/10517/presentation/20148
[4] Zentalis AACR 2022 Investor Event. Retrieved April 12, 2022, from https://ir.zentalis.com/static-files/68229106-90da-4561-8b62-8668746bb3b5
[5] AZD5305 Yields Promising Clinical and Safety Findings Across Several Solid Malignancies. Retrieved April 12, 2022, from https://www.cancernetwork.com/view/azd5305-yields-promising-clinical-and-safety-findings-across-several-solid-malignancies
[6] Therapies targeting DNA damage response show promising antitumor activity. Retrieved April 12, 2022, from https://www.mdanderson.org/newsroom/therapies-targeting-dna-damage-response-show-promising-antitumor-activity.h00-159538956.html
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