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Poster display

4055 - Preclinical characterization of the selective DNA-dependent protein kinase (DNA-PK) inhibitor VX-984 in combination with chemotherapy

Date

10 Oct 2016

Session

Poster display

Presenters

Diane Boucher

Citation

Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368

Authors

D. Boucher1, S. Hillier1, D. Newsome1, Y. Wang1, D. Takemoto1, Y. Gu1, W. Markland1, R. Hoover1, R. Arimoto1, J. Maxwell2, S.Z. Fields3, P. Charifson1, M.S. Penney4, K. Tanner1

Author affiliations

  • 1 Research, Vertex Pharmaceuticals Incorporated, 02210 - Boston/US
  • 2 Chemistry, Vertex Pharmaceuticals Incorporated, 02210 - Boston/US
  • 3 Clinical Development, Vertex Pharmaceuticals Incorporated, 02210 - Boston/US
  • 4 Discovery Biomarkers, Vertex Pharmaceuticals Incorporated, 02210 - Boston/US
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Resources

Abstract 4055

Background

The efficacy of chemotherapeutic agents such as doxorubicin and etoposide, which cause lethal DNA double-strand breaks (DSBs), is compromised by efficient repair of the damaged DNA in cancer cells. The DNA-PK is a critical regulator of the non-homologous end joining (NHEJ) repair pathway, which is responsible for repairing DSBs. Studies of nonselective inhibitors of DNA-PK have shown that cancer cells depend on DNA-PK for survival following treatment with DSB-inducing agents. However, a comprehensive characterization of DNA-PK inhibition has been hampered by a lack of selective inhibitors. Here we describe VX-984, a potent and selective inhibitor of DNA-PK, and its preclinical profile in combination with DSB-inducing chemotherapeutic agents.

Methods

VX-984 was examined as a single agent and in combination with either doxorubicin or etoposide in a panel of cancer cell lines and primary tumor explants and in mouse xenograft models.

Results

In vitro, inhibition of DNA-PK by VX-984 had potent cytotoxic activity in combination with doxorubicin and etoposide in established cancer cell lines and in primary tumor explants from ovarian and endometrial cancers (doxorubicin) and small cell lung cancer (etoposide). Bliss synergy scores of ≤23% (strong synergy) were observed for doxorubicin and etoposide in the presence of VX-984. Further, the activity observed with VX-984 was associated with enhanced DNA damage as measured by phosphorylated Kruppel-associated protein (pKAP1) and phosphorylated histone H2AX (gamma-H2AX), consistent with failed DSB repair. In vivo, VX-984 significantly enhanced the efficacy of pegylated liposomal doxorubicin (PLD) in an ovarian cancer patient-derived xenograft model as well as in cancer cell line xenograft models.

Conclusions

These data provide evidence that inhibition of DNA-PK by VX-984 enhances the efficacy of DSB-inducing agents in preclinical models and support the use of VX-984 in combination with agents such as PLD for the treatment of ovarian and endometrial cancers. VX-984 is currently in a Phase 1 clinical trial in combination with PLD.

Clinical trial identification

Preclinical (no registered clinical trial).

Legal entity responsible for the study

Vertex Pharmaceuticals Incorporated

Funding

Vertex Pharmaceuticals Incorporated

Disclosure

D. Boucher, S. Hillier, D. Newsome, Y. Wang, D. Takemoto, Y. Gu, W. Markland, R. Hoover, R. Arimoto, J. Maxwell, S.Z. Fields, P. Charifson, M.S. Penney, K. Tanner: Is an employee of Vertex Pharmaceuticals Incorporated and may own stock or stock options in that company.

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