Current Topics in Medicinal Chemistry - Volume 12, Issue 1, 2012

This first issue of Vol. 12 of “Current Topics in Medicinal Chemistry” comes at a time of increasing change within both the pharmaceutical industry and medicinal chemistry. Currently 22 of the top 25 selling drugs are reported to be generic, lacking the composition of matter patent protection that characterizes the early phase of the life cycle for any successful new product launch in the area of small-molecule therapeutics. The remaining three of the top 25 are expected to become generic by the year 2015. Other new drugs will eventually enter into this top tier of pharmaceutical sales, but the sobering fact is that the pharmaceutical industry is now more akin to industries that deal in commodities, in much the same way that the agricultural chemical industry is today. Medicinal chemistry is an enormously rewarding intellectual enterprise that has tremendous positive impact upon public health. However, in general, knowledge itself and the transfer of information has become dependent not only on the human imagination, but also how fast a person can type into a computer with broad-band access to the internet. The specialized training and dedication required to receive proficiency as a medicinal chemist has been complemented and amplified by this rapid access to knowledge, taken together with better tools and methods to carry out parallel synthesis and compound library screening. There continues to be no better time than now to be a medicinal chemist, exploring the interface of structure and function. Atypical drug targets are now investigated to a greater extent, such as nucleic acid binding proteins and the protein- protein interface. A greater appreciation of the merits of phenotypic screening, even in the absence of complete understanding of molecule mechanism of action, has also emerged in some quarters. I wish to thank the Guest Editors and Section Editors of CTMC for their dedication, initiative, and hard work, and the many authors of the various manuscripts that appear in CTMC. I also thank Ambreen Wasim, Dr. Mahmood Alam and Dr. Matthew Honan of Bentham Science Publishers for support and encouragement, and Associate Editor Ms. Rhoda Joseph for editorial and administrative support.

The incidence of cutaneous melanoma is rapidly increasing across the world. Treatment of metastatic melanoma is very difficult. One of the most promising strategies is based on the fact that melanoma cells are immunogenic and stimulate the endogenous production of anti-tumor T cells. This special issue of Current Topics in Medicinal Chemistry, “The Medicinal Chemistry of Melanoma” covers different novel therapeutic modalities in the treatment of metastatic melanoma. This special issue starts with a review by Sapoznik et al. on the potential value of CEACAM1 (Carcinoembryonic antigenrelated cell adhesion molecule 1) as a melanoma biomarker and therapeutic target. Melanoma patients with active disease have high serum levels of soluble CEACAM1. Clinical relevance of CEACAM1 as a biomarker has been discussed. Based on invitro, in-vivo and patients-derived data authors developed an anti-human CEACAM1 monoclonal antibody, which blocks CEACAM1 homophilic interactions and inhibits melanoma progression in human melanoma-xenografted mice. The research team led by Professor Jacob Schechter suggests that CEACAM1 can be a novel target for anti-melanoma immuno-interventions. In the next article, Ferrucci et al. reviewed newly identified tumour antigens as promising cancer vaccine targets in the treatment of metastatic melanoma. This in-depth review of novel and contemporary antigen-targeted vaccination strategies in the treatment of melanoma has two parts. The first part discusses vaccine modalities targeting MAGE-A3 and the Cancer testis (CT) antigens while the second part gives a comprehensive overview on vaccine strategies based on Heat shock proteins. Ferrucci et al. suggests tailored therapy for each melanoma patient chosen on the basis of the gene alterations identified in the single tumour. In the following contribution, an overview of the importance of angiogenesis in melanoma and future directions for antiangiogenic strategies in the management of melanoma was presented. This extensive review discusses different molecularly targeted anti-angiogenic strategies to inhibit angiogenesis in melanoma according to their targets: agents targeting proangiogenic ligands, monoclonal antibodies interrupting pro-angiogenic pathways, VEGF-Trap (soluble VEGF receptor), small molecule kinase inhibitors, drugs targeting MMPs and Integrins and anti-angiogenic agents with other mechanisms of action (agents with actions beyond the VEGF(R) axis). In his review Gartel summarized recent data on anticancer drug-induced apoptosis in human melanoma cells and discussed different proteasome inhibitors used alone or in combination with other drugs to inducing efficient, caspase-dependent and caspase-independent apoptosis in melanoma cells. This review provides important information needed for designing more efficient combinations of anticancer drugs against melanoma.....

CEACAM1 adhesion molecule is broadly expressed, participates in pivotal cellular and immunological processes and is involved in cancer. Originally identified as a tumor suppressor, it is now known that in several cancers, including malignant melanoma, CEACAM1 expression correlates with tumor progression and poor survival. Here we review the findings connecting CEACAM1 to malignant melanoma, encompassing in-vitro, in-vivo and patients-derived data. A CEACAM1-mediated mechanism used by melanoma cells to evade immune attack is described in detail. Finally, the potential value of CEACAM1 as a melanoma biomarker and therapeutic target is being discussed.

Immunogenicity of tumour cells, immunomodulation and direct targeting of signalling pathways are promising avenues and matter of dated and innovative research in melanoma. Unfortunately, tumour cells are considered to be antigenic, but not immunogenic, either due to presentation of weakly recognized antigens or to the inability of the immune system to recognize them. However, spontaneous complete remission can be rarely observed in patients affected by melanoma, which are mainly attributed to the immune response against the tumour. Also, an elevated frequency of spontaneous humoral immune responses against tumour antigens was occasionally found in patients. These data confirm the existence of an interaction of the immune system with the tumour which can be used as a promising pathway for intervention and incorporates all portions of the immune system. The cancer immunotherapy approach is based on artificial activation of the immune system against the tumour and groups several types of treatments including immunization/vaccination but also modulation of immunity by cytokines or antibodies. Immunization approaches could either be based on undefined tumour antigens (e.g. whole tumour cells, tumour cell lysates, or tumour-antigen enriched fractions) or aimed at eliciting T-cell responses against specific tumour antigens. Novel and contemporary antigen-targeted therapy strategies, mainly directed to Cancer Testis and Heat Shock Proteins, leading to a possible active immunization against melanoma through Tcell specific activation, are discussed in this review.

Metastatic melanoma has a very poor prognosis and systemic therapies - both cytotoxic and biological - have not improved outcome in this disease so far. For this reason, novel therapeutic strategies are urgently required. Angiogenesis represents a relevant process to modulate in melanoma, as pro-angiogenic ligands and their receptors are overexpressed and have been found to correlate with disease progression and prognosis. The angiogenic axis may be targeted at many different levels, which are still being defined. This article presents an overview of the importance of angiogenesis in melanoma and draws attention to some of the key molecules that are currently being targeted rationally within clinical studies. We discuss a number of anti-angiogenic and anti-vascular agents and their mechanisms of action. An overview of the efficacy and toxicity of these treatments in clinical trials performed so far in melanoma is presented and future directions for anti-angiogenic strategies in melanoma are considered.

The sensitivity of cancer cells to apoptosis induced by anticancer drugs in vitro may be a predictor of their sensitivity to these drugs in vivo. In this review I summarize recent data describing anticancer drug-induced apoptosis in human melanoma cells. Proteasome inhibitors alone, or in combination with other drugs, efficiently induce apoptosis in melanoma cells. It has been shown that apoptosis induced by proteasome inhibitors is linked to suppression of transcription factor FoxM1 and upregulation of the proapoptotic Noxa protein. In addition, proteasome inhibitors stabilize the antiapoptotic Mcl-1 protein, and its suppression leads to more robust apoptosis in melanoma cells. Drugs targeting B-Raf (BAY 54-9085) or IKKb (BMS-345541) have been tested in melanoma cell lines, and it has been shown that the proapoptotic activity of both drugs depends on the inhibition of NF-kB in melanoma cells. A synthetic analog of dsRNA in complex with a polycation stimulated autophagy via induction of dsRNA helicase MDA-5 followed by apoptosis that was partially modulated by Noxa. These data may provide important information needed for designing more efficient combinations of anticancer drugs against melanoma.

In-transit metastases occur in approximately 3% of melanoma patients, can be very symptomatic and survival in this group may be prolonged. Regional chemotherapy with melphalan delivered by isolated limb perfusion (ILP) or isolated limb infusion (ILI) are effective treatment options which are generally well tolerated. ILI is a less invasive and simpler alternative to ILP. ILI is tolerated better than ILP, though is probably less effective. Complete response rates are 45- 69% for ILP and 23-44% for ILI. The limb is often warmed to lower temperatures in ILI compared to ILP and the limb becomes progressively more hypoxic and acidotic during ILI, each of these parameters potentially having an effect on outcome. ILP & ILI are used primarily as palliative options when excision of in-transit metastases is unfeasible but can be used as an adjunctive procedure to surgery, for other tumour types such as merkel cell carcinoma, and can be repeated if indicated. For ILI correction of melphalan dose for ideal body weight has been shown to substantially decrease the rates of severe local toxicity while maintaining complete response rates, but overall response rate is reduced. Combination treatment with tumour necrosis factor α has been used with variable outcomes and new combinations with buthionine sulfoximine and ADH-1 are being investigated.

Ipilimumab, a fully human monoclonal antibody that binds to CTLA-4 (cytotoxic T lymphocyte-associated antigen 4), is the new hope in the treatment of patients with advanced melanoma. Anti-CTLA-4 antibodies enhance T cell responses in vitro and in vivo and activate proliferation of tumour-specific T cells. The blockade of CTLA-4 by ipilimumab leads to immune-mediated tumor regression. Ipilimumab has been studied in metastatic melanoma in a number of clinical trials. Recently, a phase III, multi-center, randomized, double-blind trial showed a significant improvement in overall survival in patients with advanced melanomas treated with ipilimumab. Thus, ipilimumab was the first drug to demonstrate effect on overall survival in patients with metastatic melanoma. However, patients treated with ipilimumab develop various immune-related adverse events (irAEs), which are associated with objective and durable clinical responses. Use of new immune-related response criteria is recommended in patients on ipilimumab therapy to avoid premature treatment discontinuation. Further research is necessary to elucidate role of ipilimumab in adjuvant setting as well as in synergy with other novel modalities for the treatment of metastatic melanoma.