Therapies targeting DNA damage response show promising antitumor activity

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Results from the first clinical trial showed two drugs that target the pathway to DNA damage (DDR) in cancer patients — ATR inhibitor elimusertib and PARP inhibitor AZD5305 — are safe and clinically useful in the treatment of patients with strong development. Senior Researcher Timothy Yap, MBBS, Ph.D., associate professor of Cancer Research, today presented new data from experiments at the American Cancer Research Center (AACR) 2022 Annual Conference.

“DDR designs complex networks that detect and repair damage to DNA, such as two stranded wires and duplicate stress,” Yap explains. “However, when DDR defects occur, it promotes negligence cancer cell proliferation also allows cells to avoid apoptosis. Studies suggest that PARP1 selectors and ATR inhibitors, which block the two major key pathways of the DDR signal path, are a group of newer drugs that offer greater therapeutic potential. patients with cancer cells that carry genetic mutations in DDR processes. “

Expansion testing of ATR inhibitors demonstrates enhanced clinical performance on DDR defects.CT006 Data Center)

In the Phase Ib expansion test, elimusertib — a potent and selective ATR inhibitor — showed signs of cancer prevention over the range.advanced malignant tumors with various DDR clearing modifications.

ATR is an important part of the DDR network that is activated by DNA damage or duplicate stress. By binding to ATR and blocking the signal generated by ATR, ATR inhibitors prevent activation of DNA damage, disrupt DNA damage and stop the growth of tumor cells, Yap explained.

In the study, 143 patients with malignant neoplasms associated with various variables of DDR degradation – including 45, 24 gynecological diseases. colorectal cancer, 19 HER2-negative breast cancers, 19 castration-resistant prostate cancers, and 36 advanced cancers with loss of alternative DDR protein ATM — gain at least one dose of elimusertib. Thirty-two patients with ATM protein loss and / or mutations were placed in the intensive care unit of the study.

The most commonly associated drug ≥3 emergencies (TEAEs) are blood disorders, including anemia (65.7%) and neutropenia (47.6%). In general, these TEAEs of leukemia are highly variable and can be controlled with bone dissection or reduction in support measures, and soon lead to permanent treatment discontinuation. Alternatively the three-day and 11-day rest schedules, which have also been examined, may reduce the risk of coronary heart disease and provide an alternative alternative that will be further evaluated in the next elimusertib study.

Elimusertib has clinical benefits along with disease management of at least 16 weeks in approximately 35% of patients enrolled within three days on, four-week enlargement, with positive responses observed in various types of cancer. The results showed lasting clinical benefit over six months in 27.8% of patients with ovarian cancer, including those with platinum-based resistance and those who had previously received PARP inhibitors. In patients with ATM loss, the best overall response included partial RECIST response in 8.9% of patients and RECIST stable disease in 55.9% of patients, with long-term clinical benefit> months. 6 in 26.5% of patients.

“As we observe persistent and persistent responses in patients with ATM changes as well Price BRCA1 same to you Price BRCA2 side effects, including patients previously treated with PARP inhibitors, further studies are needed to further identify genetic therapies to predict what patients may benefit from elimusertib monotherapy, ”he said. Yap. PARP inhibitor niraparib and with inhibitor PD-1 pembrolizumab. “

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The next selective PARP1 inhibitor demonstrates excellent clinical functionality with enhanced profile (CT007 Data Center)

Results from Phase I / IIa test PETRA show that AZD5305, a potent and selective PARP1 inhibitor and inhibitor, achieves the desired target and interesting clinical function with improved profile. The intended treatment demonstrates improved efficacy and clearance above the target than can be achieved with first-generation PARP inhibitors.

In addition to blocking the enzymatic activity of PARP, primary PARP inhibitors bind PARP1 and PARP2 – two repair proteins that activate the DDR pathway – to DNA damage sites to prevent DNA repair and to selectively kill cancer cells. . However, a large number of evidence suggests that inhibition and capture of PARP1 is only required for artificial death in cancer patients with homologous retinal detachment (HRR).

“By selective inhibition and detection of PARP1, AZD5305 achieved greater antitumor effect in pathogenesis and subtypes, more sustained inhibition and improved endurance compared to primary PARP1 / 2 inhibitors in preclinical samples, said Yap. “These exciting experimental results of AZD5305 show that we can build on the initial success of PARP inhibitors by providing important clinical evidence for this common strategy. various pathogens with AZD5305. “

In the first class, the first experiments in humans, the researchers registered and treated 61 patients with advanced breast, ovarian, prostate or pancreatic cancer containing germline or somatic. Price BRCA1 / 2, PALB2 or RAD51C / DDownload: AZD5305.

Of the 40 patients evaluated, 10 received minimal RECIST responses and 11 received stable RECIST in doses, additional forms and mutations and were independent from the initial use of the PARP inhibitor. .

The highest ≥3 TEAE scores, regardless of cause, were anemia (14.8%), followed by neutropenia (6.6%) and thrombocytopenia (3.3%). Only two patients (3.3%) required bone reduction after treatment for 3 thrombocytopenia associated with type 1 thrombocytopenia. treatment or discontinuation of treatment. Overall, AZD5305 is well tolerated with lower rates of heart attack and stroke compared to first-generation PARP inhibitors.

The drugs have a strong and long-lasting therapeutic effect at all bone levels, measured by inhibiting poly ADP-ribosylation (PARylation), indicating that AZD5305 results in a maximum target of at least 90%.

Researchers are currently conducting randomized trials to evaluate the effect of the drug on PARP-naïve inhibitors and to enhance the concentration of joint pathways, including trastuzumab deruxtecan and datopotamab deruxtecan.

The ATR RP-3500 inhibitor demonstrates safety and primary clinical benefit

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