Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 144Author(s): Jamie R. Friedman, Stephen D. Richbart, Justin C. Merritt, Haley E. Perry, Kathleen C. Brown, Austin T. Akers, Nicholas A. Nolan, Cathryn D. Stevenson, John D. Hurley, Sarah L. Miles, Maria T. Tirona, Monica A. Valentovic, Piyali Dasgupta Cytotoxic chemotherapy is the mainstay of cancer treatment. Conventional chemotherapeutic agents do not distinguish between normal and neoplastic cells. This leads to severe toxic side effects, which may necessitate the discontinuation of treatment in some patients. Recent research has identified key molecular events in the initiation and progression of cancer, promoting the design of targeted therapies to selectively kill tumor cells while sparing normal cells. Although, the side effects of such drugs are typically milder than conventional chemotherapies, some off-target effects still occur. Another serious challenge with all chemotherapies is the acquisition of chemoresistance upon prolonged exposure to the drug. Therefore, identifying supplementary agents that sensitize tumor cells to chemotherapy-induced apoptosis and help minimize drug resistance would be valuable for improving patient tolerance and response to chemotherapy. The use of effective supplementary agents provides a twofold advantage in combination with standard chemotherapy. First, by augmenting the activity of the chemotherapeutic drug it can lower the dose needed to kill tumor cells and decrease the incidence and severity of treatment-limiting side effects. Second, adjuvant therapies that lower the effective dose of chemotherapy may delay/prevent the development of chemoresistance in tumors. Capsaicinoids, a major class of phytochemical compounds isolated from chili peppers, have been shown to improve the efficacy of several anti-cancer drugs in cell culture and animal models. The present chapter summarizes the current knowledge about the chemosensitizing activity of capsaicinoids with conventional and targeted chemotherapeutic drugs, highlighting the potential use of capsaicinoids in novel combination therapies to improve the therapeutic indices of conventional and targeted chemotherapeutic drugs in human cancers.
Abstract: Publication date: Available online 13 June 2019Source: Advances in Cancer ResearchAuthor(s): Rocío G. Sampayo, Mina J. Bissell Since the introduction of the cancer stem cell (CSC) hypothesis, accumulating evidence shows that most cancers present stem-like niches. However, therapies aimed at targeting this niche have not been as successful as expected. New evidence regarding CSCs hierarchy, similarities with normal tissue stem cells and cell plasticity might be key in understanding their role in cancer biology and how to efficiently eliminate them. In this Chapter, we discuss what is known in breast and prostate CSCs from their initial discoveries to the current therapeutic efforts in the field. Future challenges towards better CSC identification and isolation strategies will be key to shed light into how CSCs could accurately be targeted in combination to traditional therapies to ultimately prolong patient survival.
Abstract: Publication date: Available online 10 June 2019Source: Advances in Cancer ResearchAuthor(s): Zachary Wilmer Reichenbach, Mary Grace Murray, Reshu Saxena, Daniel Farkas, Erika G. Karassik, Alena Klochkova, Kishan Patel, Caitlin Tice, Timothy M. Hall, Julie Gang, Henry P. Parkman, Sarah J. Ward, Marie-Pier Tétreault, Kelly A. Whelan Esophageal squamous cell carcinoma (ESCC) is among the most deadly forms of human malignancy characterized by late stage diagnosis, metastasis, therapy resistance and frequent recurrence. Clinical management of ESCC remains challenging and the disease presently lacks approved targeted therapeutics. However, emerging data from recent clinical and translational investigations hold great promise for future progress toward improving patient outcomes in this deadly disease. Here, we review current clinical perspectives in ESCC epidemiology, pathophysiology, and clinical care, highlighting recent advances with potential to impact ESCC prevention, diagnosis and management. We further provide an overview of recent translational investigations contributing to our understanding of the molecular mechanisms underlying ESCC development, progression and therapy response, including insights gained from genetic studies and various murine model systems. Finally, we discuss future perspectives in the clinical and translational realms, along with remaining hurdles that must be overcome to eradicate ESCC.
Abstract: Publication date: Available online 6 June 2019Source: Advances in Cancer ResearchAuthor(s): Aras Toker, Pamela S. Ohashi The unprecedented success of immune checkpoint inhibitors has given rise to a rapidly growing number of immuno-oncology agents undergoing preclinical and clinical development and an exponential increase in possible combinations. Defining a clear rationale for combinations by identifying synergies between immunomodulatory pathways has therefore become a high priority. Immunosuppressive regulatory T cells (Tregs) within the tumor microenvironment (TME) represent a major roadblock to endogenous and therapeutic tumor immunity. However, Tregs are also essential for the maintenance of immunological self-tolerance, and share many molecular pathways with conventional T cells including cytotoxic T cells, the primary mediators of tumor immunity. Hence the inability to specifically target and neutralize Tregs within the TME of cancer patients without globally compromising self-tolerance poses a significant challenge. Here we review recent advances in the characterization of tumor-infiltrating Tregs with a focus on costimulatory and inhibitory receptors. We discuss receptor expression patterns, their functional role in Treg biology and mechanistic insights gained from targeting these receptors in preclinical models to evaluate their potential as clinical targets. We further outline a framework of parameters that could be used to refine the assessment of Tregs in cancer patients and increase their value as predictive biomarkers. Finally, we propose modalities to integrate our increasing knowledge on Treg phenotype and function for the rational design of checkpoint inhibitor-based combination therapies. Such combinations have great potential for synergy, as they could concomitantly enhance cytotoxic T cells and inhibit Tregs within the TME, thereby increasing the efficacy of current cancer immunotherapies.
Abstract: Publication date: Available online 24 April 2019Source: Advances in Cancer ResearchAuthor(s): Swadesh K. Das, Devanand Sarkar, Luni Emdad, Paul B. Fisher With few exceptions, metastasis is the terminal stage of cancer with limited therapeutic options. Metastasis consists of numerous phenotypic and genotypic alterations of cells that are directly and indirectly induced by multiple intrinsic (cellular) and extrinsic (micro-environmental) factors. To metastasize, a cancer cell often transitions from an epithelial to mesenchymal morphology (EMT), modifies the extracellular matrix, forms emboli and survives in the circulation, escapes immune surveillance, adheres to sites distant from the initial tumor and finally develops a blood supply (angiogenesis) and colonizes in a secondary niche (a micrometastasis). Scientific advances have greatly enhanced our understanding of the precise molecular and genetic changes, operating independently or collectively, that lead to metastasis. This review focuses on a unique gene, melanoma differentiation associated gene-9 (also known as Syntenin-1; Syndecan Binding Protein (sdcbp); mda-9/syntenin), initially cloned and characterized from metastatic human melanoma and shown to be a pro-metastatic gene. In the last two decades, our comprehension of the diversity of actions of MDA-9/Syntenin on cellular phenotype has emerged. MDA-9/Sytenin plays pivotal regulatory roles in multiple signaling cascades and orchestrates both metastatic and non-metastatic events. Considering the relevance of this gene in controlling cancer invasion and metastasis, approaches have been developed to uniquely and selectively target this gene. We also provide recent updates on strategies that have been successfully employed in targeting MDA-9/Syntenin resulting in profound pre-clinical anti-cancer activity.
Abstract: Publication date: Available online 23 April 2019Source: Advances in Cancer ResearchAuthor(s): Xuan Mo, Sarah Preston, M. Raza Zaidi Cutaneous malignant melanoma is one of the few major cancers that continue to exhibit a positive rate of increase in the developed world. A wealth of epidemiological data has undisputedly implicated ultraviolet radiation (UVR) from sunlight and artificial sources as the major risk factor for melanomagenesis. However, the molecular mechanisms of this cause-and-effect relationship remain murky and understudied. Recent efforts on multiple fronts have brought unprecedented expansion of our knowledge base on this subject and it is now clear that melanoma is caused by a complex interaction between genetic predisposition and environmental exposure, primarily to UVR. Here we provide an overview of the effects of the macroenvironment (UVR) on the skin microenvironment and melanocyte-specific intrinsic (mostly genetic) landscape, which conspire to produce one of the deadliest malignancies.
Abstract: Publication date: Available online 23 April 2019Source: Advances in Cancer ResearchAuthor(s): Jie Zhang, Zhi-wei Ye, Danyelle M. Townsend, Chanita Hughes-Halbert, Kenneth D. Tew At the intersection of genetics, biochemistry and behavioral sciences, there is a largely untapped opportunity to consider how ethnic and racial disparities contribute to individual sensitivity to reactive oxygen species and how these might influence susceptibility to various cancers and/or response to classical cancer treatment regimens that pervasively result in the formation of such chemical species. This chapter begins to explore these connections and builds a platform from which to consider how the disciplines can be strengthened further.
Abstract: Publication date: Available online 12 April 2019Source: Advances in Cancer ResearchAuthor(s): Holly Fowle, Ziran Zhao, Xavier Graña PP2A is a highly conserved eukaryotic serine/threonine protein phosphatase of the PPP family of phosphatases with fundamental cellular functions. In cells, PP2A targets specific subcellular locations and substrates by forming heterotrimeric holoenzymes, where a core dimer consisting of scaffold (A) and catalytic (C) subunits complexes with one of many B regulatory subunits. PP2A plays a key role in positively and negatively regulating a myriad of cellular processes, as it targets a very sizable fraction of the cellular substrates phosphorylated on Ser/Thr residues. This review focuses on insights made toward the understanding on how the subunit composition and structure of PP2A holoenzymes mediates substrate specificity, the role of substrate modulation in the signaling of cellular division, growth, and differentiation, and its deregulation in cancer.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 143Author(s): Amrita Basu, Ganesan Ramamoorthi, Yongsheng Jia, Jon Faughn, Doris Wiener, Sabrina Awshah, Krithika Kodumudi, Brian J. Czerniecki Breast cancer, one of the leading causes of death in women in the United States, challenges therapeutic success in patients due to tumor heterogeneity, treatment resistance, metastasis and disease recurrence. Knowledge of immune system involvement in normal breast development and breast cancer has led to extensive research into the immune landscape of breast cancer and multiple immunotherapy clinical trials in breast cancer patients. However, poor immunogenicity and T-cell infiltration along with heightened immunosuppression in the tumor microenvironment have been identified as potential challenges to the success of immunotherapy in breast cancer. Oncodrivers, owing to their enhanced expression and stimulation of tumor cell proliferation and survival, present an excellent choice for targeted immunotherapy development in breast cancer. Loss of anti-tumor immune response specific to oncodrivers has been reported in breast cancer patients as well. Dendritic cell vaccines have been tested for their efficacy in generating anti-tumor T-cell response against specific tumor-associated antigens and oncodrivers and have shown improved survival outcome in patients. Here, we review the current status of immunotherapy in breast cancer, focusing on dendritic cell vaccines and their therapeutic application in breast cancer. We further discuss future directions of breast cancer immunotherapy and potential combination strategies involving dendritic cell vaccines and existing chemotherapeutics for improved efficacy and better survival outcome in breast cancer.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 143Author(s): Manny D. Bacolod, Francis Barany, Paul B. Fisher Recent reports describe how genome-wide transcriptional analysis of cancer tissues can be exploited to identify molecular signatures of immune infiltration in cancer. We hypothesize that immune infiltration in cancer may also be defined by changes in certain epigenetic signatures. In this context, a primary objective is to identify site-specific CpG markers whose levels of methylation may be highly indicative of known transcriptional markers of immune infiltration such as GZMA, PRF1, T cell receptor genes, PDCD1, and CTLA4. This has been accomplished by integrating genome-wide transcriptional expression and methylation data for different types of cancer (melanoma, kidney cancers, lung cancers, gliomas, head and neck cancer). Our findings establish that cancers of related histology also have a high degree of similarity in immune-infiltration CpG markers. For example, the epigenetic immune infiltration signatures in lung adenocarcinoma (LUAD), mesothelioma (MESO), lung squamous cell carcinoma (LUSC), and head and neck squamous cell carcinoma (HNSC) are distinctly similar. So are glioblastoma multiforme (GBM) and brain lower grade glioma (LGG); and kidney renal papillary cell carcinoma (KIRP) and kidney renal clear cell carcinoma (KIRC). Kidney chromophobe (KICH), on the other hand has markers that are unique to this cohort. The strong relationships between immune infiltration and CpG methylation (for certain sites) in cancer tissues were not observed upon integrated analysis of publicly available cancer cell line datasets. Results from comparative pathways analyses offer further justification to methylation at certain CpG sites as being indicators of cancer immune infiltration, and possibly of predicting patient response to immunotherapeutic drugs. Achieving this target objective would significantly enhance therapeutic outcomes employing immunotherapy through focused patient-centric personalized medicine.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 143Author(s): Claire Buchta Rosean, Tzu-Yu Feng, Francesca N. Azar, Melanie R. Rutkowski Humans are a colonized with trillions of commensal microorganisms which exert a profound effect on normal host physiology and immune function through an abundance of genetic and metabolic by-products. Although the commensal microbiome has beneficial functions to host physiology, perturbations of the composition of the commensal microbiome or the homeostatic mucosal environment can lead to the induction of immune pathology and systemic inflammation. In the context of cancer progression or response to immune therapy, this inflammation can be detrimental, resulting in tumor growth and the promotion of immune suppression. On the other hand, significant associations have been identified whereby certain commensal microorganisms are able to enhance T cell function or are required for tumor control in cancer patients treated with certain immune therapies and chemotherapies. The focus of this chapter is to highlight the role of the commensal microbiome during tumor progression and in response to immune therapies.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 143Author(s): Chunqing Guo, Shixian Chen, Wenjie Liu, Yibao Ma, Juan Li, Paul B. Fisher, Xianjun Fang, Xiang-Yang Wang Fundamental metabolic pathways are essential for mammalian cells to provide energy, precursors for biosynthesis of macromolecules, and reducing power for redox regulation. While dysregulated metabolism (e.g., aerobic glycolysis also known as the Warburg effect) has long been recognized as a hallmark of cancer, recent discoveries of metabolic reprogramming in immune cells during their activation and differentiation have led to an emerging concept of “immunometabolism.” Considering the recent success of cancer immunotherapy in the treatment of several cancer types, increasing research efforts are being made to elucidate alterations in metabolic profiles of cancer and immune cells during their interplays in the setting of cancer progression and immunotherapy. In this review, we summarize recent advances in studies of metabolic reprogramming in cancer as well as differentiation and functionality of various immune cells. In particular, we will elaborate how distinct metabolic pathways in the tumor microenvironment cause functional impairment of immune cells and contribute to immune evasion by cancer. Lastly, we highlight the potential of metabolically reprogramming the tumor microenvironment to promote effective and long-lasting antitumor immunity for improved immunotherapeutic outcomes.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 143Author(s): Rachel E. O’Neill, Xuefang Cao Cancer remains the leading cause of death worldwide. Traditional treatments such as surgery, radiation, and chemotherapy have had limited efficacy, especially with late stage cancers. Cancer immunotherapy and targeted therapy have revolutionized how cancer is treated, especially in patients with late stage disease. In 2013 cancer immunotherapy was named the breakthrough of the year, partially due to the established efficacy of blockade of CTLA-4 and PD-1, both T cell co-inhibitory molecules involved in tumor-induced immunosuppression. Though early trials promised success, toxicity and tolerance to immunotherapy have hindered long-term successes. Optimizing the use of co-stimulatory and co-inhibitory pathways has the potential to increase the effectiveness of T cell-mediated antitumor immune response, leading to increased efficacy of cancer immunotherapy. This review will address major T cell co-stimulatory and co-inhibitory pathways and the role they play in regulating immune responses during cancer development and treatment.
Abstract: Publication date: 2019Source: Advances in Cancer Research, Volume 143Author(s): Arsen Osipov, Adrian Murphy, Lei Zheng Cancer is a worldwide medical problem with significant repercussions on individual patients and societies as a whole. In order to alter the outcomes of this deadly disease the treatment of cancer over the centuries has undergone a unique evolution. However, utilizing the best treatment modalities and achieving cures or long-term durable responses have been inconsistent and limited, that is until recently. Contemporary research has highlighted a fundamental gap in our understanding of how we approach treating cancer, by revealing the intricate relationship between the immune system and tumors. In this atmosphere, the growth of immunotherapy has not only forever changed our understanding of cancer biology, but the manner by which we treat patients. It's paradigm shifting success has led to the approval of over 10 different immunotherapeutic agents, including checkpoint inhibitors, vaccine-based therapies, oncolytic viruses and T cell directed therapies for nearly 20 different indications across countless tumor types. Despite the breakthroughs that have occurred in the field of immunotherapy, it has not been the panacea for all cancers. With a deeper understanding of the immune system we have been able to peer into tumor immune escape and therapy resistance. Simultaneously this understanding has paved the way for the investigation and development of novel immune system altering agents and combinatorial therapies. In this chapter we review the immune system and its intricate relationship with cancer, the evolution of immunotherapy, its current landscape, and future directions in the context of resistance mechanisms and the challenges faced by immunotherapy against cancer.
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