mk-1775 and Carcinoma

Uterine serous carcinoma is a distinct histologic subtype of endometrial cancer with an aggressive phenotype, poor prognosis, and limited therapeutic options. A previous proof-of-concept phase II trial of the Wee1 inhibitor adavosertib in uterine serous carcinoma demonstrated evidence of durable clinical activity.. To evaluate the efficacy of adavosertib in women with recurrent or persistent uterine serous carcinoma.. We hypothesize that adavosertib will demonstrate significant clinical activity, as measured by objective response rate, in women with recurrent or persistent uterine serous carcinoma.. Eligible participants will receive adavosertib monotherapy until disease progression or unacceptable toxicity, starting at the recommended phase II dosing of adavosertib 300 mg daily days 1 through 5 and 8 through 12 of a 21-day cycle. Participants will have restaging studies every 6 weeks for the first 48 weeks and then every 9 weeks thereafter.. Patients with histologically confirmed recurrent or persistent uterine serous carcinoma, including endometrial carcinoma of mixed histology where the serous component comprises at least 10% of the tumor, and who have received at least one prior platinum-based chemotherapy regimen for the management of uterine serous carcinoma, are eligible for inclusion in the trial. Participants must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Participants with carcinosarcoma are not eligible.. The primary endpoint is the objective response rate by RECIST 1.1 criteria, as determined by blinded independent central review.. Approximately 120 patients will be enrolled in this trial.. Study completion and presentation of results are projected to be at the end of 2022.. ClinicalTrials.gov: NCT04590248.

Topics: Carcinoma; Cell Cycle Proteins; Clinical Trials, Phase II as Topic; Female; Humans; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidinones; Uterine Neoplasms

Nasopharyngeal carcinoma (NPC) is a rare but highly invasive cancer. As radiotherapy is the primary treatment for NPC, this offers a rationale to investigate if uncoupling the DNA damage responses can sensitize this cancer type. The G2 DNA damage checkpoint is controlled by a cascade of protein kinases: ATM/ATR, which phosphorylates CHK1/CHK2, which in turn phosphorylates WEE1. A number of small molecule inhibitors have been developed against these kinases as potential therapeutic agents. Here we demonstrated that compare to that in immortalized nasopharyngeal epithelial cells, ATR, CHK1, and WEE1 were overexpressed in NPC cell lines. Inhibitors of these kinases were unable to promote extensive mitotic catastrophe in ionizing radiation-treated NPC cells, indicating that they are not very effective radiosensitizer for this cancer. In the absence of prior irradiation, however, mitotic catastrophe could be induced with inhibitors against CHK1 (AZD7762) or WEE1 (MK-1775). NPC cells were more sensitive to WEE1 inactivation than nasopharyngeal epithelial cells. Targeting CHK1 and WEE1 together induced more extensive mitotic catastrophe than the individual components alone. Taken together, our results show that NPC cells depend on CHK1 and WEE1 activity for growth and that inhibitors of these kinases may serve as potential therapeutics for NPC.

Topics: Animals; Ataxia Telangiectasia Mutated Proteins; Carcinoma; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Checkpoint Kinase 1; DNA Damage; Flow Cytometry; G2 Phase; Gene Expression Regulation, Neoplastic; Green Fluorescent Proteins; HeLa Cells; Humans; Mice; Mice, Inbred BALB C; Mitosis; Nasopharyngeal Carcinoma; Nasopharyngeal Neoplasms; Neoplasm Invasiveness; Neoplasm Transplantation; Nuclear Proteins; Phosphorylation; Protein Kinase Inhibitors; Protein Kinases; Protein-Tyrosine Kinases; Pyrazoles; Pyrimidines; Pyrimidinones; RNA Interference; Thiophenes; Urea