adavosertib (AZD1775) / AstraZeneca, Merck (MSD) - LARVOL DELTA

Curcumin Alone and Combined With PI3K Inhibitors Elicits Positive Effects on Oropharyngeal Cancer Cell Lines Regardless of HPV Status. (PubMed, Anticancer Res) - "Curcumin alone led to dose-dependent responses and when combined with BYL719, positive effects were revealed, as they were when it was combined with MK-1775 or PD-0332991, suggesting a potential use of some of these combinations for HPV+ OPSCC."

Journal • Preclinical • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CDC27 • CDK4 • FGFR3 • PARP1 • PIK3CA

ADAVOSERTIB, A WEE1 INHIBITOR, AS A NOVEL SENOLYTICS, TARGETS THE VULNERABILITY OF LIVER CANCER INDUCED BY EPIRUBICIN (DDW 2024) - "Our study revealed that among the six common chemotherapy drugs (epirubicin, paclitaxel, sorafenib, regorafenib, oxaliplatin, irinotecan), the synergic effect of epirubicin and the WEE1 inhibitor Adavosertib on tumor proliferation in vivo and in vitro was the best. The sustained DNA damage induced by epirubicin promoted cell senescence and activated the cGAS-STING pathway to up-regulate SASP secretion, in which inflammatory factor A induced T cell infiltration in the tumor tissue microenvironment, thus playing a stronger tumor killing role. Epirubicin-resistant liver cancer cells showed increased stemness expression, but could still be targeted and killed by Adavosertib, indicating the potential utility of Adavosertib as a treatment for refractory liver cancer."

IO biomarker • Gastrointestinal Cancer • Hepatocellular Cancer • Hepatology • Liver Cancer • Oncology • Solid Tumor

A phase II trial of AZD1775 plus carboplatin-paclitaxel in squamous cell lung cancer (SqCLC). (ASCO 2024) - P2 | "Clinical Trial Registration Number: NCT02513563"

P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

Integrated drug profiling and CRISPR screening identify BCR::ABL1-independent vulnerabilities in chronic myeloid leukemia. (PubMed, Cell Rep Med) - "We employ genome-wide CRISPR-Cas9 screening for six drugs, and mediator complex, apoptosis, and erythroid-lineage-related genes are identified as key resistance hits for TKIs, whereas the Wee1 inhibitor AZD1775 and mepacrine exhibit distinct resistance profiles. KCTD5, a consistent TKI-resistance-conferring gene, is found to mediate TKI-induced BCR::ABL1 ubiquitination. In summary, we delineate potential mechanisms for primary TKI resistance and non-BCR::ABL1-targeting drugs, offering insights for optimizing CML treatment."

Journal • Chronic Myeloid Leukemia • Hematological Malignancies • Leukemia • Oncology • Targeted Protein Degradation • ABL1 • CD34

NEW INSIGHTS INTO MK 1775 RESISTANCE: DUAL INHIBITION OF WEE1 AND CHK1 IN UGC TREATMENT (DDW 2024) - "Combining MK 1775 with a highly potent and specific CHK1 inhibitor CHIR 124 effectively inhibited CHK1 kinase activity and abrogated STAT3 indued drug resistance. Our study underscores the potential of combining WEE1 and CHK1 inhibitors to effectively combat MK1775 resistance in UGC, offering a promising direction for improved treatment strategies and patient outcomes in these challenging malignancies."

Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Gastrointestinal Disorder • Oncology • CHEK1 • STAT3 • WEE1

The novel WEE1i, APR-1051, is a potentially well tolerated and effective treatment for cyclin E-overexpressing cancers (AACR 2024) - "One challenge for two of the leading WEE1i, AZD1775 and ZN-c3, has been the observed off-targeting of PLK family members, namely, PLK1, PLK2 and PLK3. APR-1051 is now progressing through IND-enabling studies. Together, these findings underscore the potential of APR-1051 as a novel WEE1i for the treatment of Cyclin E-overexpressing cancers."

Oncology • Ovarian Cancer • Solid Tumor • CCNE1 • PLK2

Sequential treatment with PARPi and WEE1i minimizes T cell DNA damage and enhances its immune response (AACR 2024) - "However, the effect of sequential treatment on T lymphocytes and anti-cancer immunity remains largely unknown.Methods and T cells were treated with 25 μM olaparib, or 250 nM AZD1775, or olaparib combined with AZD1775 (concurrent group) for 48h, or olaparib for 24h followed by AZD1775 for 24h (sequential group) in vitro. This study demonstrated that targeting PARP and/or WEE1 impaired the T cell viability and led to DNA damage. However, administrating PARPi and WEE1i sequentially diminished this inhibitory effect on T cells on the premise of ensuring their anti-tumor effect. These data provide strong rational for the further investigation on exploring the clinical significance of sequential treatment with PARPi and WEE1i."

Oncology • Ovarian Cancer • Solid Tumor • CASP3 • CXCL10 • IFNB1

Overcoming MK1775 resistance in upper gastrointestinal cancers with combined WEE1 and CHK1 inhibition (AACR 2024) - "Notably, combining the WEE1 inhibitor with the CHK1 inhibitor CHIR124 effectively inhibited CHK1 kinase activity and abrogated STAT3 phosphorylation, DNA binding, and transcriptional activity in UGC cells. Our study underscores the potential of combining WEE1 and CHK1 inhibitors to effectively combat MK1775 resistance in UGC, offering a promising direction for improved treatment strategies and patient outcomes in these challenging malignancies."

Esophageal Adenocarcinoma • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Oncology • Solid Tumor • WEE1

Activity of PARP1-selective inhibitor SNV-001 in models of HRD cancers as monotherapy and in combination (AACR 2024) - "SNV-001 showed greater efficacy at lower doses compared to olaparib at 100 mg/kg or at equivalent doses of AZD9574...SNV-001 enhanced cytotoxicity of the DNA-damaging agent topotecan or carboplatin in Capan-1 (BRCA2mut) and HCC1395 (BRCA1mut) cells. Synergy was seen between SNV-001 and cell cycle check point inhibitors camonsertib (ATRi) or adavosertib (WEE1i) in DLD1 (BRCA2 -/-) and UWB1.289 (BRCA1mut) cells, as DNA damage induced by PARP1 trapping relies on cell cycle modulation for repair. Combination of SNV-001 with polymerase theta inhibitor ART558 or USP1 inhibitor KSQ4279 exhibited synergistic effects in DLD1 (BRCA2 -/-) or UWB1.289 (BRCA1mut) cells...Current data highlight a potential strategy for improving treatment efficacy and overcoming resistance. Further clinical investigations are warranted to validate this combination strategy."

Monotherapy • Oncology • BRCA1 • BRCA2 • HRD • PARP2 • USP1

ACR-2316: A potentially first-in-class, potent, selective WEE1/PKMYT1 inhibitor rationally designed for superior single agent activity through synergistic disruption of cell cycle checkpoints (AACR 2024) - "ACR-2316 is more selective than adavosertib, azenosertib, and lunresertib based on >200 kinases profiled by AP3 and 468 kinases assessed by KINOMEscan...In conclusion, ACR-2316 is a potent, selective dual WEE1/PKMYT1 inhibitor with superior single-agent activity compared to clinical WEE1 or PKMYT1 inhibitors. ACR-2316 is progressing through IND-enabling studies in preparation for clinical monotherapy development."

Oncology • Ovarian Cancer • Solid Tumor • CDK1 • CDK2 • CHEK1 • PKMYT1 • PLK1

WEE1 inhibition prevents and overcomes resistance to KRAS inhibitors in lung cancer by enhancing MCL1-mediated apoptosis (AACR 2024) - "In vivo efficacy studies in combination with sotorasib and AZD1775 also demonstrated remarkable tumor regression and durable response in both CDX and PDX models. Our results suggest that the WEE1-MCL1 axis plays an important role in both the initial therapeutic efficacy and the acquired resistance to KRAS inhibitors. These findings could pave the way for a novel therapeutic strategy for KRAS G12C mutant NSCLC."

Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ANXA5 • BCL2L11 • CASP3 • CASP7 • KRAS • MCL1 • WEE1

Co-clinical endometrial cancer (EC) patient-derived organoids (PDO) to assess functional effects of replication stress (RS)-targeting agents (AACR 2024) - "We describe the successful establishment of co-clinical EC PDOs for functional evaluation of sensitivity to RS targeting agents."

Clinical • Colorectal Cancer • Endometrial Cancer • Endometrial Serous Adenocarcinoma • Gynecologic Cancers • Oncology • Sarcoma • Solid Tumor • Uterine Cancer • TP53

Adavosertib Before Surgery in Treating Patients With Advanced High Grade Ovarian, Fallopian Tube, or Primary Peritoneal Cancer (clinicaltrials.gov) - P1 | N=38 | Active, not recruiting | Sponsor: M.D. Anderson Cancer Center | Trial completion date: Dec 2023 ➔ Dec 2026 | Trial primary completion date: Dec 2023 ➔ Dec 2026

Metastases • Surgery • Trial completion date • Trial primary completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Solid Tumor • MUC16

Safety, tolerability, pharmacokinetics, and antitumor activity of adavosertib in Japanese patients with advanced solid tumors: A phase I, open-label study. (PubMed, Cancer Treat Res Commun) - P1 | "Adavosertib 200 mg once daily was well tolerated in this patient population and no safety concerns were raised. Exposure increased in a slightly more than dose-proportional manner and limited antitumor activity was shown."

Journal • Metastases • PK/PD data • Febrile Neutropenia • Hematological Disorders • Neutropenia • Oncology • Solid Tumor

Testing AZD1775 as a Potential Targeted Treatment in Cancers With BRCA Genetic Changes (MATCH-Subprotocol Z1I) (clinicaltrials.gov) - P2 | N=35 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Jun 2024 ➔ Jun 2025 | Trial primary completion date: Jun 2024 ➔ Jun 2025

Trial completion date • Trial primary completion date • Breast Cancer • Hematological Malignancies • HER2 Breast Cancer • Lymphoma • Multiple Myeloma • Oncology • Ovarian Cancer • Solid Tumor • BRCA • BRCA1 • BRCA2 • HER-2

Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality. (PubMed, Sci Bull (Beijing)) - "The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug."

Journal • Synthetic lethality • Gallbladder Cancer • Gastrointestinal Cancer • Hepatology • Oncology • Solid Tumor • ER • TP53

Transforming Growth Factor Beta and Alveolar Rhabdomyosarcoma: A Challenge of Tumor Differentiation and Chemotherapy Response. (PubMed, Int J Mol Sci) - "We next highlight current chemotherapy strategies, including a combination of the FDA-approved drugs vincristine, actinomycin D, and cyclophosphamide (VAC); cabozantinib; bortezomib; vinorelbine; AZD 1775; and cisplatin. Lastly, we discuss chemotherapy agents that target the differentiation of tumor cells in ARMS, which include all-trans retinoic acid (ATRA) and 5-Azacytidine. Improving our understanding of the role of signaling pathways, such as TGF-β1, in the development of ARMS tumor cells differentiation will help inform more tailored drug administration in the future."

Journal • Review • Oncology • Rhabdomyosarcoma • Sarcoma • Solid Tumor • PAX3 • PAX7 • TGFB1

A phase 2 study of the WEE1 inhibitor AZD1775 in SETD2-deficient advanced solid tumor malignancies. (ASCO 2023) - P2 | "AZD1775 given as monotherapy failed to achieve an objective response in SETD2-altered RCC and other solid tumor malignancies. However, a subset of pts derived clinical benefit as manifested by tumor regressions and/or durable stable disease. Evaluation of AZD1775 in combination with other DNA damage-inducing agents that cause replication stress may be warranted, potentially with the integration of the H3K36me3 mark as a biomarker for patient selection."

Metastases • P2 data • Anemia • Clear Cell Renal Cell Carcinoma • Genito-urinary Cancer • Hematological Disorders • Immunology • Neutropenia • Oncology • Renal Cell Carcinoma • Solid Tumor • SETD2

Identification of m6A-associated autophagy genes in non-alcoholic fatty liver. (PubMed, PeerJ) - "Ultimately, we found that the TF-mRNA network included FOXP1-GOPC, ATF1-RAB1A and other relationship pairs, and eight therapeutic agents such as R-406 and adavosertib were predicted based on the TBK1. However, it is critical to note that these findings, although consequential, demonstrate correlations rather than cause-and-effect relationships. As such, more research is required to fully elucidate the underlying mechanisms and validate the clinical relevance of these feature genes."

Journal • Hepatology • Metabolic Dysfunction-Associated Steatotic Liver Disease • ATF1 • FOXP1 • TBK1

A Precision Therapy Targeting Replication Stress in Hepatocellular Carcinoma by Wee1 inhibition. (APASL 2024) - "Our study proposes a novel classification and treatment strategy for HCC based on tumor RS levels, potentially enriching precision medicine with direct clinical implications."

Gastrointestinal Cancer • Hepatocellular Cancer • Oncology • Solid Tumor • HRD

Adavosertib, Radiation Therapy, and Temozolomide in Treating Patients With Newly Diagnosed or Recurrent Glioblastoma (clinicaltrials.gov) - P1 | N=74 | Active, not recruiting | Sponsor: National Cancer Institute (NCI)

Trial completion date • Brain Cancer • CNS Tumor • Glioblastoma • Oncology • Solid Tumor • CASP3 • MGMT • TP53 • WEE1

Gemcitabine Hydrochloride With or Without WEE1 Inhibitor MK-1775 in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer (clinicaltrials.gov) - P2 | N=124 | Active, not recruiting | Sponsor: National Cancer Institute (NCI) | Trial completion date: Feb 2024 ➔ Feb 2025

Combination therapy • Monotherapy • Trial completion date • Fallopian Tube Cancer • Oncology • Ovarian Cancer • Ovarian Serous Adenocarcinoma • Peritoneal Cancer • Sarcoma • Solid Tumor • TP53

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=200 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Recruiting ➔ Active, not recruiting | N=600 ➔ 200

Enrollment change • Enrollment closed • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Prostate Cancer Biomarker Enrichment and Treatment Selection (clinicaltrials.gov) - P2 | N=600 | Recruiting | Sponsor: Canadian Cancer Trials Group | Trial completion date: Jul 2024 ➔ Dec 2025 | Trial primary completion date: Dec 2023 ➔ Dec 2024

Biomarker • Trial completion date • Trial primary completion date • Genito-urinary Cancer • Oncology • Prostate Cancer • Solid Tumor

Testing AZD1775 inC Combination With Radiotherapy and Chemotherapy in Cervical, Upper Vaginal and Uterine Cancers (clinicaltrials.gov) - P1 | N=10 | Terminated | Sponsor: National Cancer Institute (NCI) | Active, not recruiting ➔ Terminated; Inadequate accrual rate

Combination therapy • Trial termination • Cervical Cancer • Gastrointestinal Cancer • Gynecologic Cancers • Oncology • Solid Tumor • Uterine Cancer • Vaginal Cancer