All Publications


  • Haploinsufficiency networks identify targetable patterns of allelic deficiency in low mutation ovarian cancer. Nature communications Delaney, J. R., Patel, C. B., Willis, K. M., Haghighiabyaneh, M., Axelrod, J., Tancioni, I., Lu, D., Bapat, J., Young, S., Cadassou, O., Bartakova, A., Sheth, P., Haft, C., Hui, S., Saenz, C., Schlaepfer, D. D., Harismendy, O., Stupack, D. G. 2017; 8: 14423-?

    Abstract

    Identification of specific oncogenic gene changes has enabled the modern generation of targeted cancer therapeutics. In high-grade serous ovarian cancer (OV), the bulk of genetic changes is not somatic point mutations, but rather somatic copy-number alterations (SCNAs). The impact of SCNAs on tumour biology remains poorly understood. Here we build haploinsufficiency network analyses to identify which SCNA patterns are most disruptive in OV. Of all KEGG pathways (N=187), autophagy is the most significantly disrupted by coincident gene deletions. Compared with 20 other cancer types, OV is most severely disrupted in autophagy and in compensatory proteostasis pathways. Network analysis prioritizes MAP1LC3B (LC3) and BECN1 as most impactful. Knockdown of LC3 and BECN1 expression confers sensitivity to cells undergoing autophagic stress independent of platinum resistance status. The results support the use of pathway network tools to evaluate how the copy-number landscape of a tumour may guide therapy.

    View details for DOI 10.1038/ncomms14423

    View details for PubMedID 28198375

    View details for PubMedCentralID PMC5316854

  • Nelfinavir is effective against human cervical cancer cells in vivo: a potential treatment modality in resource-limited settings. Drug design, development and therapy Davis, M. A., Delaney, J. R., Patel, C. B., Storgard, R. n., Stupack, D. G. 2016; 10: 1837–46

    Abstract

    The standard treatment for cervical cancer in developed countries includes surgery and chemoradiation, with standard of care lagging in developing countries. Even in the former case, treatment frequently yields recalcitrant tumors and women succumb to disease. Here we examine the impact of nelfinavir, an off-patent viral protease inhibitor, which has shown promise as an antineoplastic agent.We evaluated the morphological and proliferative effects of the autophagy-stressing drug nelfinavir in normal and cisplatin-resistant cervical cancer cells. Immunofluorescent validation of autophagy markers was performed and the impact of nelfinavir in an in vivo model of tumor growth was determined.Nelfinavir exhibits cytotoxicity against both cisplatin-sensitive and -resistant ME-180 human cervical cancer cells in vitro and in vivo. Immunoblotting and immunofluorescence showed an expression of the autophagy marker LC3-II in response to nelfinavir treatment.Nelfinavir, now available as an inexpensive generic orally dosed agent (Nelvir), is cytotoxic against cervical cancer cells. It acts by burdening the autophagy pathway to impair tumor cell survival and a modest induction of apoptosis. While further studies are needed to elucidate the optimal method of application of nelfinavir, it may represent an appealing global option for the treatment of cervical cancer.

    View details for DOI 10.2147/DDDT.S102241

    View details for PubMedID 27330277

    View details for PubMedCentralID PMC4898046

  • A strategy to combine pathway-targeted low toxicity drugs in ovarian cancer ONCOTARGET Delaney, J. R., Patel, C., McCabe, K. E., Lu, D., Davis, M., Tancioni, I., von Schalscha, T., Bartakova, A., Haft, C., Schlaepfer, D. D., Stupack, D. G. 2015; 6 (31): 31104-31118

    Abstract

    Serous Ovarian Cancers (SOC) are frequently resistant to programmed cell death. However, here we describe that these programmed death-resistant cells are nonetheless sensitive to agents that modulate autophagy. Cytotoxicity is not dependent upon apoptosis, necroptosis, or autophagy resolution. A screen of NCBI yielded more than one dozen FDA-approved agents displaying perturbed autophagy in ovarian cancer. The effects were maximized via combinatorial use of the agents that impinged upon distinct points of autophagy regulation. Autophagosome formation correlated with efficacy in vitro and the most cytotoxic two agents gave similar effects to a pentadrug combination that impinged upon five distinct modulators of autophagy. However, in a complex in vivo SOC system, the pentadrug combination outperformed the best two, leaving trace or no disease and with no evidence of systemic toxicity. Targeting the autophagy pathway in a multi-modal fashion might therefore offer a clinical option for treating recalcitrant SOC.

    View details for DOI 10.18632/oncotarget.5093

    View details for Web of Science ID 000363185200064

    View details for PubMedID 26418751

    View details for PubMedCentralID PMC4741591