Clinical Cancer Drugs - Volume 2, Issue 1, 2015

Clinical application of immune checkpoint blockades has dramatically changed the landscape of cancer immunotherapy, especially in the field of metastatic melanoma. For the first time in the history of treatment of melanoma, immunotherapies using immune checkpoint blockades such as anti-Cytotoxic T-Lymphocyte Antigen-4 (CTLA-4) and Program Death-1 (PD-1) antibodies have consistently shown regression of metastatic tumors with survival benefit. However, the treatment of metastatic melanoma with immune checkpoint blockades has also brought new scientific and clinical challenges to treating physicians and clinical investigators. Such new challenges include: (1) how should we manage/ minimize serious immune-related adverse events without sacrificing anti-cancer effects?, (2) how should we choose one immune checkpoint blockade over others and in what sequence?, (3) how should we combine the immune checkpoint blockade with other cancer treatments such as chemotherapy, radiotherapy and signal blockades?, and (4) how can we predict clinical response with new immunological agents? In this review, we provide an overview of the molecular basis of new immunotherapies for metastatic melanoma and discussed potential strategies to improve the treatment outcomes using immune checkpoint blockades alone or in combination with various therapeutic modalities.

Metastatic melanoma represents an aggressive tumor with overall poor prognosis. Targeted agents and immunotherapy have become the standard of care. Approximately 50-60 % of melanomas harbor BRAF mutations. Vemurafenib and dabrafenib are BRAF inhibitors, a group of drugs that will certainly expand, and obtained FDA approval after showing increased response rate (ORR), progression free survival (PFS) and overall survival (OS) when compared to chemotherapy. Trametinib was the first MEK inhibitor approved as single agent in 2013, but when combined with BRAF inhibition, results are even improved. Immunotherapy with IL-2 received approval in 1999 based on phase II data mainly due to its potentially long term response but proved to be quite toxic. Check point inhibitors can block CTLA-4 (ipilimumab) or PD-1 (nivolumab and pembrolizumab) thus interrupting the brakes that stop the immune system against malignant cells. Long duration of response resembles that of IL-2 but with more acceptable toxicity. Given the complexity of this rapidly evolving field we will try to provide the reader with a summary of the key clinical aspects derived from the use of these new agents in daily practice.

Uveal melanoma represents the most common primary intraocular tumor in adults. However, it remains a relatively infrequent malignancy where large clinical trials are difficult to accomplish. However, during the last couple of years we have witnessed an unprecedented expansion of our understanding of this disease. New genetic and molecular pathways were found to play key roles in the development of uveal melanoma and they represent potential targets for future therapies. At the same time there were some improvements in the delineation of prognostic features as well as treatment options for metastatic disease, with both liver-directed strategies as well as targeted agents. In this review we will try to summarize and update the reader with the most relevant information in terms of its pathogenesis, clinical presentation, prognostic factors– cytogenetic and genetic profiling –, state of the art management of liver only as well as systemic metastatic disease. Finally we will also discuss current ongoing clinical trials as well as future directions in terms of research and clinical investigation.

Mucosal melanomas are rare and associated with poor prognosis. Importantly, primary mucosal melanoma is clinically and biologically different from cutaneous melanoma. Complete surgical resection is the standard of care treatment for localized melanoma. However, given the usual anatomic locations where mucosal melanomas arise, including head and neck and anorectal mucosa, resection with optimal margins is challenging and post-surgical local recurrences are not uncommon. Adjuvant radiation therapy diminishes local recurrence rate but does not seem to improve overall survival in multiple retrospective series. Although significant progress has been achieved in term of systemic treatment for patients with metastatic cutaneous and uveal melanomas, there are still no groundbreaking results for patients with mucosal melanoma. In that sense, metastatic mucosal melanoma is indeed an orphan disease. Chemotherapy in general has shown poor results. The efficacy of ipilimumab is not established yet. Targeted agents, such as imatinib or sunitinib could be a promising treatment option for patients with KIT mutations. In this review we will try to update the reader with some key points of this rare disease, especially those related to its particular clinical features, some recently discovered and potential molecular targets as well as the small number of clinical trials that support a rational approach to this disease.

Obatoclax (GX15-070) is a small molecule that binds to Bcl-2 family proteins (Bcl-2, Bcl- XL, and MCL-2) and has demonstrated efficacy in reinitiating programmed cell death. We previously demonstrated the synergistic effects of GX15-070 in combination with cytotoxic agents in rituximab sensitive and rituximab resistant models. Our aim was therefore to develop a pharmacodynamic model to characterize the degree of interaction between GX15-070 and Bortezomib (BTZ) on cells isolated from Non-Hodgkin’s Lymphoma (NHL) patients to understand the role of combination therapy. Cells were exposed to escalating concentrations of GX15-070 and BTZ for 48 hours; data were fit to pharmacodynamic model. Patient demographics, BCL-2 status, Ki67%, CD20, lifetime-rituximab dose and response to therapy were obtained for all patients and correlated with observed pharmacodynamic endpoints. The greatest degree of synergy was seen in the MCL, MZL, and untreated DLBCL-GCB. Previously un-treated B-cell lymphoma (DLBCL-ABC, DLBCL-GCB/transformed, FL) and relapsed refractory B-cell lymphoma (DLBCL-ABC, FL) demonstrate a combination shift towards a possible additive effect. The majority of the patients had DLBCL or FL, and 29% had relapsed/refractory disease. These results demonstrate synergism in NHL and may support the use of this combination in a future clinical trial.

Purpose: We have previously reported that hepatic arterial infusion chemotherapy (HAIC) prolongs the survival of patients with advanced hepatocellular carcinoma (aHCC). However, 5- fluorouracil (5-FU) has been found to exacerbate liver damage in patients with liver cirrhosis (LC). We also previously reported that HAIC might cause occult hepatotoxicity and induces fibrosis without elevation of aminotransferases. The aim of this study was to clarify the effect of glutathione (GSH) on the hepatotoxicity of HAIC in LC patients with aHCC. Methods: Forty-one adult Japanese patients with LC and aHCC underwent HAIC between 2004 and 2009 at our hospital, and achieved multiple partial responses or had stable disease. The patients were divided into two groups, which were a non-GSH group receiving HAIC alone (n = 21) and a GSH group treated with HAIC plus GSH (n = 20). HAIC was delivered via the proper hepatic artery every 5 days for 4 weeks. GSH (100 mg) was given by intravenous injection on each morning of HAIC. Results: The Child-Pugh (C-P) class was A for 12 patients from the non-GSH group and 9 patients from the GSH group, while it was B for 9 and 11 patients, respectively. In class A and B patients from the non-GSH group, the C-P score showed a significant increase after chemotherapy compared with before chemotherapy. In contrast, there was no significant change the C-P score after chemotherapy in the GSH group. There were also no significant changes in the serum markers of liver fibrosis after chemotherapy in the GSH group, although a significant increase was noted in the non-GSH group. Conclusions: In LC patients with aHCC receiving HAIC, GSH might inhibit hepatotoxicity related to occult fibrosis occurring elevation of aminotransferases.

Aside from its function in cellular homeostasis, autophagy enables cells to dispose of damaged cellular components and to recycle metabolites in response to cellular stress. Of particular interest is the context-dependent role of autophagy in cancer. Autophagy has been shown to inhibit tumor growth in the early stages of carcinogenesis, yet promotes the progression of previously established tumors. The characterization of potent, specific autophagy inhibitors with novel mechanisms of action is a very active area of research. ATG4B is one of four mammalian ATG4 orthologues and cleaves the ubiquitin-like ATG8 mammalian orthologues (e.g. pro-LC3B), a crucial step in the formation of the mature autophagosome. This review provides an overview of the role of ATG4 orthologues during autophagy, describes cancerspecific ATG4 functions and discusses the role of ATG4B inhibition as an emerging anti-cancer strategy. While available data show that impairing ATG4B typically decreases the growth of human cancer cell lines in vitro and in vivo, under certain circumstances ATG4B inhibition may also be detrimental. On the other hand, pre-clinical testing of ATG4B inhibitors and the analysis of ATG4B knockout mice suggest that ATG4B inhibition should be very well tolerated. As is the case with other autophagy inhibitors, future studies would benefit from the development of suitable predictive biomarkers of response and tools to monitor autophagy activity.