Heat shock proteins (HSPs) are a large family of molecular chaperones heavily implicated in the orchestration of cancer development and progression. Targeting them could therefore represent new hope for patients with tumors that have ultimately acquired resistance to conventional treatments.
Over recent years, a number of heat shock protein inhibitors (HSPi) have been developed and subsequently shown promise at preclinical and clinical levels. To name but one, HSP90 is an ATP-dependent molecular chaperone required for the stability of its clientele — mostly comprised of driver oncoproteins. While a number of HSP90 inhibitors are currently undergoing clinical trials for a variety of cancers, none of these novel therapeutic contenders have been approved.
Increasingly proving their potential as an alternative and efficacious anti-cancer therapy for patients with disease that has a specific molecular background or has acquired resistance to other agents, HSP90i have yet to deliver on their true promise.
Published last month as an open access Brief Communication in JNCI: Journal of the National Cancer Institute, Susana Cedrés, Medical Oncologist and Clinical Investigator of VHIO’s Thoracic Tumors & Head and Neck Group, led by Enriqueta Felip, has first-authored a case report of a patient with metastatic lung cancer with a germline BRCA1 mutation who showed exquisite sensitivity to a duo of chemotherapy drugs, cisplatin and gemcitabine, combined with HSP90i.
Susana Cedrés and co-authors from VHIO´s Thoracic Tumors, Cancer Genomics, Experimental Therapeutics, Molecular Oncology, and High Risk & Cancer Prevention Groups (headed by Enriqueta Felip, Ana Vivancos, Violeta Serra, Paolo Nuciforo and Judith Balmaña, respectively), as well as clinical investigators from the Molecular Oncology and Pathology Departments of the Vall d´Hebron University Hospital (directed by VHIO’s Director, Josep Tabernero, and Santiago Ramon y Cajal), chart a purely multidisciplinary and translational story spanning sequencing, the detection of mutational specificities, validation of the paired therapeutic approach in a PDX model, to an ongoing response to HSP90i maintenance monotherapy – post treatment with cisplatin/gemcitabine plus HSP90 blockade – for more than three years.
“Tumors with BRCA1 mutations are initially sensitive to platinum anti-cancer drugs and PARP inhibitors. Unfortunately they ultimately acquire resistance. Our patient, diagnosed with non-small cell lung cancer (NSCLC) carrying a germline BRCA1 mutation, showed an exceptional response to cisplatin/gemcitabine in combination with an HSP90 inhibitor. Our findings represent an important step in further evidencing the potential of these novel agents, in combination,” comments Susana.
“This case, along with the validation in our PDX model, demonstrates the efficacy of HSP90 blockade in a BRCA-mutated patient. This could help guide us towards more precisely identifying patients who might benefit most from this therapeutic approach,” concludes Enriqueta Felip, co-author and Principal Investigator of VHIO’s Thoracic Tumors & Head and Neck Cancer Group.
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This work was supported by the Spanish Association Against Cancer (AECC) Scientific Foundation, and partially by the Spanish Ministry of Health and Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional.
Cedrés S, Felip E, Cruz C, Martinez de Castro A, Pardo N, Navarro A, Martinez-Marti A, Remon J, Zeron-Medina J, Balmaña J, Llop-Guevara A, Miquel JM, Sansano I, Nuciforo P, Mancuso F, Serra V, Vivancos A. Activity of HSP90 Inhibiton in a Metastatic Lung Cancer Patient With a Germline BRCA1 Mutation. J Natl Cancer Inst. 2018 Feb 26. doi: 10.1093/jnci/djy012. [Epub ahead of print].