New drug targets in metastatic melanoma

Homet, Blanca; Ribas, Antoni

doi:10.1002/path.4259

Cited by 52 publications

(49 citation statements)

References 91 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[31][32][33] Unfortunately nearly all patients will develop acquired resistance. 28 The combination of BRAF and MEK inhibitors seems to delay this effect but resistance appears inevitable. Combining the high response rate of these targeted inhibitors with the durability of responses to immunotherapy was a logical approach that led to further testing of combined regimens but as mentioned previously was associated with significant toxicities.…”

Section: Discussionmentioning

confidence: 99%

“…26,27 Vemurafenib is an FDA approved BRAF inhibitor with high antitumor activity in patients with BRAF mutations based on a phase III trial. 6,28,29 Dabrafenib, a fellow BRAF inhibitor has also shown efficacy in treatment of advanced melanoma. 6,30 Trametinib, which targets MEK downstream of BRAF pathway also has been approved as has the combination of drabrafenib/trametinib.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Wyluda

Cheng

Schell

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

Drabick (2015) Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy, Cancer Biology & Therapy, 16:5, 662-670, DOI: 10.1080/15384047.2015 We report 3 cases of durable complete response (CR) in patients with BRAF-mutated metastatic melanoma who were initially treated unsuccessfully with sequential immunotherapies (high dose interleukin 2 followed by ipilimumab with or without concurrent radiation therapy). After progression during or post immunotherapy, these patients were given BRAF inhibitor therapy and developed rapid CRs. Based on the concomitant presence of autoimmune manifestations (including vitiligo and hypophysitis), we postulated that there was a synergistic effect between the prior immune therapy and the BRAF targeting agents. Accordingly, the inhibitors were gradually weaned off beginning at 3 months and were stopped completely at 9-12 months. The three patients remain well and in CR off of all therapy at up to 15 months radiographic follow-up. The institution of the BRAF therapy was associated with development of severe rheumatoid-like arthritis in 2 patients which persisted for months after discontinuation of therapy, suggesting it was not merely a known toxicity of BRAF inhibitors (arthralgias). On immunologic analysis, these patients had high levels of non-T-regulatory, CD4 positive effector phenotype T-cells, which persisted after completion of therapy. Of note, we had previously reported a similar phenomenon in patients with metastatic melanoma who failed high dose interleukin-2 and were then placed on a finite course of temozolomide with rapid complete responses that have remained durable for many years after discontinuation of temozolomide. We postulate that a finite course of cytotoxic or targeted therapy specific for melanoma given after apparent failure of prior immunotherapy can result in complete and durable remissions that may persist long after the specific cytotoxic or targeted agents have been discontinued suggesting the existence of sequence specific synergism between immunotherapy and these agents. Here, we discuss these cases in the context of the literature on synergy between conventional or targeted cytotoxic therapy and immunotherapy in cancer treatment.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Durable complete responses off all treatment in patients with metastatic malignant melanoma after sequential immunotherapy followed by a finite course of BRAF inhibitor therapy

Wyluda

Cheng

Schell

et al. 2015

Cancer Biology & Therapy

View full text Add to dashboard Cite

show abstract

“…Despite the considerable progress using targeted therapies against oncogenic BRAF and immunotherapies (22), resistance to therapies invariably develops (20,23). There is, therefore, a need for additional treatment strategies, including targeting of the metastatic process.…”

Section: Introductionmentioning

confidence: 99%

Rho Kinase Inhibitors Block Melanoma Cell Migration and Inhibit Metastasis

et al. 2015

View full text Add to dashboard Cite

There is an urgent need to identify new therapeutic opportunities for metastatic melanoma. Fragment-based screening has led to the discovery of orally available, ATP-competitive AKT kinase inhibitors, AT13148 and CCT129254. These compounds also inhibit the Rho-kinases ROCK 1 and ROCK 2 and we show they potently inhibit ROCK activity in melanoma cells in culture and in vivo. Treatment of melanoma cells with CCT129254 or AT13148 dramatically reduces cell invasion, impairing both "amoeboidlike" and mesenchymal-like modes of invasion in culture. Intravital imaging shows that CCT129254 or AT13148 treatment reduces the motility of melanoma cells in vivo. CCT129254 inhibits melanoma metastasis when administered 2 days after orthotopic intradermal injection of the cells, or when treatment starts after metastases have arisen. Mechanistically, our data suggest that inhibition of ROCK reduces the ability of melanoma cells to efficiently colonize the lungs. These results suggest that these novel inhibitors of ROCK may be beneficial in the treatment of metastasis. Cancer Res; 75(11); 2272-84. Ó2015 AACR.

show abstract

“…ExoT-induced cytotoxicity occurred across a wide range of tumour cell lines, including breast, lung, cervical and even melanoma that is largely refractory to current cytotoxic drugs in the clinical setting (Atkins et al, 2008;Flaherty et al, 2012;Homet & Ribas, 2013).…”

Section: Discussionmentioning

confidence: 99%