Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).

Plummer, Elizabeth Ruth; Dean, Emma; Trj., Evans; Greystoke, Alastair; Herbschleb, Karin H; Ranson, Malcolm R; Brown, Jennifer R.; Zhang, Y; Karan, Sharon; Pollard, John R.; Penney, Marina; Asmal, Mohammed; Fields, SZ; Middleton, Mark R.

doi:10.1200/jco.2016.34.15_suppl.2513

Cited by 28 publications

(20 citation statements)

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“…Four ATR inhibitors are now in clinical trial as monotherapy and/or in combination with DNA-damaging chemotherapy and ionising radiation. Results from a Phase I study of VX-970 (M6620) in combination with topotecan have recently been published along with other studies in abstract form [ 15 , 16 , 17 ]. These indicate that the drug is well tolerated as a single agent and in combination.…”

Section: Discussionmentioning

confidence: 99%

The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation

Middleton

Pollard

Curtin

2018

Cancers

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Ataxia telangiectasia mutated and Rad3 related kinase (ATR) signals replication stress and DNA damage to S and G2 arrest and promotes DNA repair. Mutations in p53, critical for G1 checkpoint control, are common in cancer and predicted to confer vulnerability to ATR inhibitors. Reported data on the impact of p53 status are variable possibly because of the use of unmatched cells and surrogate endpoints of survival. The cytotoxicity of VE-821 alone and its ability to potentiate radiation and gemcitabine cytotoxicity was determined in isogenic and unmatched p53 wild-type (wt) and null/mutant cells, as well as immortalised nonmalignant MCF10 (immortalised non-neoplastic) cells, by colony-forming assay. The effect on cell cycle checkpoints was determined by flow cytometry. The isogenic p53 defective cells were not more sensitive to VE-821 alone. Defective p53 consistently conferred greater chemo- and radiosensitisation, particularly at high dose levels in isogenic cells but not unmatched cells. VE-821 did not sensitise MCF10 cells. We conclude that p53 status is just one factor contributing to chemo- and radiosensitisation by ATR inhibition, the lack of chemo- or radiosensitisation in the noncancerous cells suggests an element of tumour-specificity that warrants further investigation. The greater sensitisation at high-dose irradiation suggests that ATR inhibitors may be most effective with hypofractionated radiotherapy.

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Section: Discussionmentioning

confidence: 99%

The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation

Middleton

Pollard

Curtin

2018

Cancers

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“…As expected from the predicted mechanism-based toxicity profile of an ATR inhibitor and platinum chemotherapy, myelosuppression (neutropenia and thrombocytopenia) was the most commonly observed treatment-related toxicity (68). Combination trials with VX-970 and a number of other chemotherapeutics are ongoing, including cisplatin and gemcitabine, with promising antitumor responses observed in chemotherapy-resistant patients with advanced solid cancers (69,70) ( Table 2 ). AZD6738 (AstraZeneca) is an oral ATR inhibitor currently being assessed in phase I clinical trials as monotherapy or in combination regimens with olaparib, carboplatin, radiotherapy or the immune-checkpoint inhibitor durvalumab (MEDI4736; AstraZeneca).…”

Section: Targeting Of Dna Damage Signalling Proteinsmentioning

confidence: 99%

Targeting DNA Repair in Cancer: Beyond PARP Inhibitors

et al. 2017

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Germline aberrations in critical DNA repair and DNA-damage response (DDR) genes cause cancer predisposition, while various tumors harbor somatic mutations causing defective DDR/DNA repair. The concept of synthetic lethality can be exploited in such malignancies, as exemplified by approval of poly(ADP-ribose) polymerase inhibitors for treating BRCA1/2 mutated ovarian cancers. Herein, we detail how cellular DDR processes engage various proteins that sense DNA damage, initiate signaling pathways to promote cell cycle checkpoint activation, trigger apoptosis and coordinate DNA repair. We focus on novel therapeutic strategies targeting promising DDR targets and discuss challenges of patient selection and the development of rational drug combinations.

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“… 48 , 49 The most well-known examples are the poly (ADP-ribose) polymerase inhibitors in BRCA1/2 –mutated cancers. There is an increasing catalogue of DDR pathway inhibitors that interrogate DNA damage–signaling proteins such ATM, 50 ATR, 51 DNA-PK, 52 WEE1, 53 and CHK1&2. 54 The frequency of alterations in DDR-related genes in HNSCC is approximately 8% based on the AACR GENIE database.…”

Section: New Targets or Drugs Of Interest In Hnsccmentioning

confidence: 99%

Precision Medicine in Head and Neck Cancer: Myth or Reality?

Malone

Siu

2018

Clin Med Insights Oncol

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Standard treatment in head and neck squamous cell carcinoma (HNSCC) is limited currently with decisions being made primarily based on tumor location, histology, and stage. The role of the human papillomavirus in risk stratification is actively under clinical trial evaluations. The molecular complexity and intratumoral heterogeneity of the disease are not actively integrated into management decisions of HNSCC, despite a growing body of knowledge in these areas. The advent of the genomic era has delivered vast amounts of information regarding different cancer subtypes and is providing new therapeutic targets, which can potentially be elucidated using next-generation sequencing and other modern technologies. The task ahead is to expand beyond the existent armamentarium by exploiting beyond the genome and perform integrative analysis using innovative systems biology methods, with the goal to deliver effective precision medicine-based theragnostic options in HNSCC.

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Phase I trial of first-in-class ATR inhibitor VX-970 in combination with gemcitabine (Gem) in advanced solid tumors (NCT02157792).

Cited by 28 publications

References 0 publications

The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation

The Impact of p53 Dysfunction in ATR Inhibitor Cytotoxicity and Chemo- and Radiosensitisation

Targeting DNA Repair in Cancer: Beyond PARP Inhibitors

Precision Medicine in Head and Neck Cancer: Myth or Reality?

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