Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate‐risk and high‐risk head and neck squamous cell carcinoma

Chera, Bhishamjit S.; Sheth, Siddharth; Patel, Shetal; Goldin, Dan; Douglas, Kathe; Green, Rebecca L.; Shen, Colette J.; Gupta, Gaorav P.; Moore, Dominic T.; Olson, Juneko E Grilley; Weiss, Jared

doi:10.1002/cncr.33789

Cited by 24 publications

(16 citation statements)

References 17 publications

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“…In contrast, it enhanced the cytotoxic effect of CompC in Renca cells ( Figure 5 c). Previously, the combination of Adavo with various DNA-damaging agents, including 5-fluorouracil, cisplatin, and radiation, has been reported to produce robust anti-tumor activity [ 46 , 47 ]. Adavo enhances the cytotoxic effects of 5-fluorouracil in p53-deficient human colon cancer cells, presumably by premature entry into mitosis via inhibition of Cdk1 Tyr 15 phosphorylation, induction of histone H3 phosphorylation, abrogation of DNA damage checkpoints, and G2 block [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Compound C Inhibits Renca Renal Epithelial Carcinoma Growth in Syngeneic Mouse Models by Blocking Cell Cycle Progression, Adhesion and Invasion

Lee

Ham

Hwang

et al. 2022

IJMS

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Compound C (CompC), an inhibitor of AMP-activated protein kinase, reduces the viability of various renal carcinoma cells. The molecular mechanism underlying anti-proliferative effect was investigated by flow cytometry and western blot analysis in Renca cells. Its effect on the growth of Renca xenografts was also examined in a syngeneic BALB/c mouse model. Subsequent results demonstrated that CompC reduced platelet-derived growth factor receptor signaling pathways and increased ERK1/2 activation as well as reactive oxygen species (ROS) production. CompC also increased the level of active Wee1 tyrosine kinase (P-Ser642-Wee1) and the inactive form of Cdk1 (P-Tyr15-Cdk1) while reducing the level of active histone H3 (P-Ser10-H3). ROS-dependent ERK1/2 activation and sequential alterations in Wee1, Cdk1, and histone H3 might be responsible for the CompC-induced G2/M cell cycle arrest and cell viability reduction. In addition, CompC reduced the adhesion, migration, and invasion of Renca cells in the in vitro cell systems, and growth of Renca xenografts in the BALB/c mouse model. Taken together, the inhibition of in vivo tumor growth by CompC may be attributed to the blockage of cell cycle progression, adhesion, migration, and invasion of tumor cells. These findings suggest the therapeutic potential of CompC against tumor development and progression.

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Section: Discussionmentioning

confidence: 99%

Compound C Inhibits Renca Renal Epithelial Carcinoma Growth in Syngeneic Mouse Models by Blocking Cell Cycle Progression, Adhesion and Invasion

Lee

Ham

Hwang

et al. 2022

IJMS

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“…Based on these promising studies, further phase 1 studies have investigated the combination of certain anticancer agents in specific types of cancers. In locally advanced or unresectable pancreatic cancer, adavosertib was combined with gemcitabine and radiation therapy at various doses [106], and in locally advanced head and neck cancer, it was combined with concurrent chemoradiation therapy with cisplatin [107]. Both studies demonstrated good drug tolerability with encouraging clinical outcomes for this strategy, suggesting that further studies should be conducted on adavosertib in combination with chemotherapy and radiotherapy.…”

Section: Wee1 Inhibitorsmentioning

confidence: 99%

Therapeutic Targeting of DNA Damage Response in Cancer

Choi

Lee

2022

IJMS

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DNA damage response (DDR) is critical to ensure genome stability, and defects in this signaling pathway are highly associated with carcinogenesis and tumor progression. Nevertheless, this also provides therapeutic opportunities, as cells with defective DDR signaling are directed to rely on compensatory survival pathways, and these vulnerabilities have been exploited for anticancer treatments. Following the impressive success of PARP inhibitors in the treatment of BRCA-mutated breast and ovarian cancers, extensive research has been conducted toward the development of pharmacologic inhibitors of the key components of the DDR signaling pathway. In this review, we discuss the key elements of the DDR pathway and how these molecular components may serve as anticancer treatment targets. We also summarize the recent promising developments in the field of DDR pathway inhibitors, focusing on novel agents beyond PARP inhibitors. Furthermore, we discuss biomarker studies to identify target patients expected to derive maximal clinical benefits as well as combination strategies with other classes of anticancer agents to synergize and optimize the clinical benefits.

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“…Importantly, several preclinical studies in mice also showed increased tumor delay when radiation was combined with Wee1 inhibition (55,(85)(86)(87)(90)(91)(92)(93) and several clinical trials are currently examining the efficacy of AZD1775 with radiation therapy (sometimes in combination with chemotherapy). Phase I trials produced promising results (94,95), although the combination with cisplatin prompted the need for toxicity-related dosing adjustments (95). The initial proposal that p53 status was an essential biomarker for the radiosensitization by Wee1 inhibition (55) was put into doubt by subsequent studies (89).…”

Section: Radiosensitization By Wee1 Inhibitionmentioning

confidence: 99%

Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1

Chan

Gamper

2022

Front. Oncol.

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Cancer cells typically heavily rely on the G2/M checkpoint to survive endogenous and exogenous DNA damage, such as genotoxic stress due to genome instability or radiation and chemotherapy. The key regulator of the G2/M checkpoint, the cyclin-dependent kinase 1 (CDK1), is tightly controlled, including by its phosphorylation state. This posttranslational modification, which is determined by the opposing activities of the phosphatase cdc25 and the kinase Wee1, allows for a more rapid response to cellular stress than via the synthesis or degradation of modulatory interacting proteins, such as p21 or cyclin B. Reducing Wee1 activity results in ectopic activation of CDK1 activity and drives premature entry into mitosis with unrepaired or under-replicated DNA and causing mitotic catastrophe. Here, we review efforts to use small molecule inhibitors of Wee1 for therapeutic purposes, including strategies to combine Wee1 inhibition with genotoxic agents, such as radiation therapy or drugs inducing replication stress, or inhibitors of pathways that show synthetic lethality with Wee1. Furthermore, it become increasingly clear that Wee1 inhibition can also modulate therapeutic immune responses. We will discuss the mechanisms underlying combination treatments identifying both cell intrinsic and systemic anti-tumor activities.

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Phase 1 trial of adavosertib (AZD1775) in combination with concurrent radiation and cisplatin for intermediate‐risk and high‐risk head and neck squamous cell carcinoma

Cited by 24 publications

References 17 publications

Compound C Inhibits Renca Renal Epithelial Carcinoma Growth in Syngeneic Mouse Models by Blocking Cell Cycle Progression, Adhesion and Invasion

Compound C Inhibits Renca Renal Epithelial Carcinoma Growth in Syngeneic Mouse Models by Blocking Cell Cycle Progression, Adhesion and Invasion

Therapeutic Targeting of DNA Damage Response in Cancer

Targeting the DNA Damage Response for Cancer Therapy by Inhibiting the Kinase Wee1

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