Targeting Bcl-2/Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts

Némati, Fariba; Montrion, Catherine de; Lang, Guillaume; Kraus‐Berthier, Laurence; Carita, Guillaume; Sastre-Garau, Xavier; Berniard, Aurélie; Vallerand, David; Geneste, Olivier; Plater, Ludmilla de; Lockhart, Brian P.; Desjardins, Laurence; Piperno‐Neumann, Sophie; Depil, Stéphane; Decaudin, Didier

doi:10.1371/journal.pone.0080836

Cited by 39 publications

(25 citation statements)

References 46 publications

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“…However, patient-derived xenograft (PDX)-based mouse studies with uveal melanoma tumors by Nemati et al have brought into focus alternative approaches of developing targeted therapy. 107 Those authors used well characterized PDX from primary uveal melanoma in mice to study the effect of small-molecule inhibitors of B-cell lymphoma-2/ B-cell lymphoma-extra large (Bcl-2/Bcl-XL) on uveal melanoma tumor growth. Primary uveal melanoma reportedly has high expression of the antiapoptotic protein, Bcl-2.…”

Section: Translational Approachesmentioning

confidence: 99%

Uveal melanoma: From diagnosis to treatment and the science in between

Chattopadhyay

Kim

Gombos

et al. 2016

Cancer

320

258

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Melanomas of the choroid, ciliary body, and iris of the eye are collectively known as uveal melanomas. These cancers represent 5% of all melanoma diagnoses in the United States, and their age-adjusted risk is 5 per 1 million population. These less frequent melanomas are dissimilar to their more common cutaneous melanoma relative, with differing risk factors, primary treatment, anatomic spread, molecular changes, and responses to systemic therapy. Once uveal melanoma becomes metastatic, therapy options are limited and are often extrapolated from cutaneous melanoma therapies despite the routine exclusion of patients with uveal melanoma from clinical trials. Clinical trials directed at uveal melanoma have been completed or are in progress, and data from these well designed investigations will help guide future directions in this orphan disease. Cancer 2016;122:2299-312. V C 2016 American Cancer Society.KEYWORDS: breast cancer 1-associated protein 1 (BAP1), choroidal melanoma, diagnosis, guanine nucleotide binding protein a11 (GNA11), guanine nucleotide-binding protein Q polypeptide (GNAQ), ocular melanoma, review, science, treatment, uveal melanoma. BACKGROUND AND EPIDEMIOLOGYUveal melanoma is the most common primary intraocular malignancy. The uveal tract is the pigmented layer of the globe encompassing the iris, ciliary body, and choroid (Fig. 1). The terms choroidal melanoma and ocular melanoma are alternative terms for this cancer, because most of the uveal tract is choroidal. However, the term ocular melanoma should be avoided, because it implies the inclusion of conjunctival and adnexal melanomas, which behave and are managed like cutaneous rather than uveal primaries. Approximately 1500 new cases of uveal melanoma are diagnosed in the United States each year, most commonly arising in the choroid followed by the ciliary body. Iris melanomas are the least common location for uveal melanoma (Fig. 2).1 Although the disease has no sex preference, it is more common in middle-aged Caucasians (median age at presentation, 58 years). Risk factors include the presence of a choroidal nevus, which can be observed in 7% to 8% of the Caucasian population. Certain skin conditions, such as dysplastic nevus syndrome and nevus of Ota, are also associated with uveal melanoma.2 It has been theorized by some investigators that exposure to ultraviolet radiation increases the risk of this neoplasia, but this has not been definitively proven. Whereas certain somatic mutations are associated with neoplastic growth and distant metastasis, the malignancy is not inherited in a traditional genetic fashion, although it is believed that individuals who have germline breast cancer 1 (BRCA1)-associated protein 1 (BAP1) mutations are at higher risk for uveal and cutaneous melanoma as well as mesothelioma and renal cancers.

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Section: Translational Approachesmentioning

confidence: 99%

Uveal melanoma: From diagnosis to treatment and the science in between

Chattopadhyay

Kim

Gombos

et al. 2016

Cancer

320

258

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“…The comparison of serial UM xenografts to the original tumor showed that xenografts are genetically stable over in vivo passages and maintain the genetics features of the original human UM [382]. Despite the limits of a low rate of engraftment and growth delay after initial transplantation, panels of UM PDXs have been employed to test combinations of targeted therapies [383, 384]. …”

Section: Animal Modelsmentioning

confidence: 99%

The biology of uveal melanoma

Amaro

Gangemi

Piaggio

et al. 2017

Cancer Metastasis Rev

192

193

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Uveal melanoma (UM), a rare cancer of the eye, is distinct from cutaneous melanoma by its etiology, the mutation frequency and profile, and its clinical behavior including resistance to targeted therapy and immune checkpoint blockers. Primary disease is efficiently controlled by surgery or radiation therapy, but about half of UMs develop distant metastasis mostly to the liver. Survival of patients with metastasis is below 1 year and has not improved in decades. Recent years have brought a deep understanding of UM biology characterized by initiating mutations in the G proteins GNAQ and GNA11. Cytogenetic alterations, in particular monosomy of chromosome 3 and amplification of the long arm of chromosome 8, and mutation of the BRCA1-associated protein 1, BAP1, a tumor suppressor gene, or the splicing factor SF3B1 determine UM metastasis. Cytogenetic and molecular profiling allow for a very precise prognostication that is still not matched by efficacious adjuvant therapies. G protein signaling has been shown to activate the YAP/TAZ pathway independent of HIPPO, and conventional signaling via the mitogen-activated kinase pathway probably also contributes to UM development and progression. Several lines of evidence indicate that inflammation and macrophages play a pro-tumor role in UM and in its hepatic metastases. UM cells benefit from the immune privilege in the eye and may adopt several mechanisms involved in this privilege for tumor escape that act even after leaving the niche. Here, we review the current knowledge of the biology of UM and discuss recent approaches to UM treatment.

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“…BM-1197 caused reversible platelet reduction in mice at highly efficacious doses. Servier also generated a nanomolar affinity dual BCL-2/BCL-X L inhibitor, S44563, which exerted promising inhibitory efficacy in patient-derived uveal melanoma cell lines and xenografts and enhanced sensitivity of small cell lung cancer to radiation [21,22]. …”

Section: Bh3 Mimetics Of Anti-apoptotic Bcl-2 Proteinsmentioning

confidence: 99%

Progress in targeting the BCL-2 family of proteins

Garner

López

Reyna

et al. 2017

Current Opinion in Chemical Biology

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The network of protein-protein interactions among the BCL-2 protein family plays a critical role in regulating cellular commitment to mitochondrial apoptosis. Anti-apoptotic BCL-2 proteins are considered promising targets for drug discovery and exciting clinical progress has stimulated intense investigations in the broader family. Here, we discuss recent developments in small molecules targeting anti-apoptotic proteins and alternative approaches to targeting BCL-2 family interactions. These studies advance our understanding of the role of BCL-2 family proteins in physiology and disease, providing unique tools for dissecting these functions. The BCL-2 family of proteins is a prime example of targeting protein-protein interactions and further chemical biology approaches will increase opportunities for novel targeted therapies in cancer, autoimmune and aging-associated diseases.

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Targeting Bcl-2/Bcl-XL Induces Antitumor Activity in Uveal Melanoma Patient-Derived Xenografts

Cited by 39 publications

References 46 publications

Uveal melanoma: From diagnosis to treatment and the science in between

Uveal melanoma: From diagnosis to treatment and the science in between

The biology of uveal melanoma

Progress in targeting the BCL-2 family of proteins

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