Book Volume 9
Page: i-iii (3)
Author: Atta-ur-Rahman and M. Iqbal Choudhary
Page: iv-v (2)
Author: Atta-ur-Rahman and M. Iqbal Choudhary
Page: 1-63 (63)
Author: Nhi Nguyen, Stina George Fernandes, Ekta Khattar and Yinghui Li
Traditionally, anti-cancer treatments mainly focus on chemotherapies, radiation therapy and surgery. However, these treatments are limited in terms of their specificity for targeting only cancer cells. DNA damaging chemotherapy is one of the most common treatment modalities of cancer. Current progress of targeted therapy that relies on DNA damage response (DDR) in cancer offers a vast therapeutic window by specifically targeting DDR functions in patient specific tumours. Recent developments in immunotherapy – therapy that boosts the body’s immune system to fight against cancer cells, have shown promising results. Currently, different approaches of immunotherapies such as cytokine, antibody, oncolytic virus, adoptive cell transfer therapies or cancer vaccination have made significant progress in treating different cancer types. This paper seeks to provide an overview of the recent developments of drugs targeting DDR and various immunotherapeutic approaches, with specific focus on the anti-CD19 CAR-T cell therapy. Finally, the paper will give a perspective on future directions of DDR therapy, CAR-T cell therapy as well as the combination of different cancer therapies for effective cancer treatment regime.
Over the past few years, the decipher of different DNA damage response mechanisms enables the development of novel inhibitors for cancer treatment. Furthermore, recent advances in genomic editing technologies and scientific discoveries reveal important roles of the immune system in the context of cancer development. This also prompts the plethora of drug developments that have vast potential in the treatment of different types of cancer diseases. This paper will give an overview of recent drug developments in chemotherapeutic agents targeting DNA damage response as well as recent immunotherapies that have been successful in the treatment of human cancers. The contents discussed in the paper are summarized in (Fig. 1).
Page: 64-90 (27)
Author: Meredith McKean and Rodabe N. Amaria
Approximately 40% of patients with cutaneous melanoma have an activating mutation in BRAF kinase, leading to constitutive activation of the mitogen-activated protein kinase pathway and unregulated cell growth. Selective inhibitors of the mutated BRAF kinase produce response rates of approximately 50%, median progression free survival of 6 to 7 months, and 5-year OS rate of 20% in patients with BRAF V600E/K mutant metastatic melanoma. BRAF blocking therapies work rapidly, with responses seen within 2 weeks after therapy initiation, and they are associated with generally mild toxicities. Most patients, however, develop resistance to BRAF inhibition. Dual inhibition of BRAF and MEK has demonstrated improved efficacy over single agent therapy with a median overall survival of 25.1 months and long-term follow-up showing 23% five-year overall survival rate. The FDA approved single agent therapy with BRAF inhibitor dabrafenib and in combination with MEK inhibitor trametinib for use in patients with BRAF V600 mutated metastatic melanoma in 2014. Now either targeted therapy or immune checkpoint inhibitors are selected for front-line treatment in the metastatic setting based on individual patient factors since there is no evidence to demonstrate a superior regimen. Sequencing of these agents is currently being explored in clinical trials. Studies are also ongoing to assess the benefit of targeted therapy with BRAF and MEK inhibitors in conjunction with immunotherapy. Additionally, oncogenic BRAF mutations have been identified in other solid tumors including papillary thyroid, colon, and non-small cell lung cancers. BRAF inhibition has been explored in these malignancies leading to FDA approval in non-small cell lung cancer and ongoing investigation of combination therapies. Methods: Pubmed and MESH databases were searched for literature published between 2010-2018 using the keywords of melanoma, dabrafenib, vemurafenib, trametinib, and BRAF.
Page: 91-113 (23)
Author: Maria Ines Vaccaro and Claudio Daniel Gonzalez
Macroautophagy is a physiological cellular process that sequesters senescent or damaged organelles and proteins in autophagosomes for recycling of their products. Autophagy is also involved in the removal of cells that have undergone classical type 1 apoptosis. Hence, autophagy can be generally considered as a protector of cells against various stressors and a cellular response to routine wear-and-tear. On the other hand, autophagy may also lead to a form of non-apoptotic cell death, which is called type 2 programmed cell death. Thus, autophagy can either protect cells or promote cell death, depending on the cellular and environmental context. So far, contradictory data are available regarding the activity of autophagy and its regulation in cancer cells. In nonmalignant healthy tissues, autophagy seems to suppress the transition of normal to cancer cells. In addition, an exaggerated autophagy rate might drive neoplastic cells to death through several mechanisms, many of which are still not elucidated. Nevertheless, experimental evidence pointed at autophagy as a cancer cell mechanism to survive under adverse environmental conditions, or as a defective programmed cell death mechanism that favors cancer cell resistance to treatment. In the end, the role of autophagy in cancer is complex and it seems to depend on histology, stage, and multiple genetic variations and epigenetic changes. The tumor surrounding microenvironment exhibits a very complex set of interactions with autophagy at cancer tissues and represents another factor that is able to regulate tumor cell-kinetics and growth, as well as the response to therapies. In summary, while there is certain evidence that autophagy may act as a barrier to tumor initiation in some specific tissues, there is mounting evidence that autophagy has a significant pro-tumorigenic role in established cancers. Cancer therapies, including chemotherapy, radiotherapy and immunotherapy, are also associated with relevant changes into the autophagy intensity and flow. Some antineoplastic agents increase the autophagy rate; some other are associated with a reduction of the autophagy rate. Autophagy may modulate anticancer immunity by affecting several cellular and humoral mechanisms involved at these critical processes. Immunotherapeutic agents recently introduced in oncology clearly induce relevant modifications on autophagy flow in several tumor types. In addition, it has been demonstrated that certain non-antineoplastic drugs may exert some autophagy inducing effect on cancer cells. On the other hand, other agents block autophagy flow synergizing with the effect of some antineoplastic agents. Autophagy modulation is at this moment, a clear target for further development of cancer therapy. A description of the mechanisms that regulate autophagy in cancer cells and their surrounding micro-environment and the potential consequences of the pharmacologically induced modifications of these processes, constitute the main objective of this chapter.
Page: 114-192 (79)
Author: Tijana Stankovic, Ana Podolski-Renic, Jelena Dinic and Milica Pesic
Collateral sensitivity (CS) is a phenomenon in which development of multidrug resistance (MDR) in cancer cells confers higher sensitivity to other drugs compared to parental cells. This means that along with advantages, MDR cancer cells may adopt certain weaknesses. Therefore, MDR phenotype became a target for the development of new drugs, termed MDR-selective compounds. These compounds may exploit the overexpression of ATP Binding Cassette (ABC) transporters, directly acting on transporters’ ATPase function or indirectly acting on mechanisms independent of transporters activity. Herein, we review the current findings regarding the specific mechanisms of MDR selective drugs, their potential use in combination with other drugs or chemotherapeutics and perspectives in finding new anti-cancer options for MDR treatment.
Page: 193-233 (41)
Author: Mahendar Porika, Radhika Tippani and Nazneen Firdous
A common hallmark of human cancers is the over expression of telomerase, a ribonucleoprotein complex that is responsible for maintaining the length and integrity of chromosome ends and often directly correlated with the uncontrolled growth of cancer cells. Telomerase activity is present in 85-90% of all cancers, but absent in normal cells, which makes telomerase a good marker for cancer diagnosis and prognosis. Also, telomerase inhibition can be used as a novel anticancer therapy with reduced probability of toxicity than present antimalignancy drugs. However, current treatments used for cancer such as radiation, anti-hormonal therapy, surgery and chemotherapy using synthetic drugs, have been reported to produce various side effects. Therefore, it is crucial to reveal the beneficial effects of natural compounds with lesser side effects on normal cells and potential anticancer activity. In recent years, several natural molecules have been discovered so far that arrest proliferation of cancer cells by inhibiting telomerase. In this book chapter, we highlighted the effect of natural compounds on cancer cell proliferation, telomerase activity and their mechanism of action.
Page: 234-286 (53)
Author: Aditi Gangopadhyay and Aparna Gangopadhyay
CDKs (Cyclin-Dependent Kinases) are protein kinases that regulate cell cycle progression. In cancer cells, which are characterised by unregulated proliferation, CDK expression and activity are often deregulated. CDKs are potential therapeutic targets in cancer therapy. However, the inhibition of CDKs is a complicated affair and has been the subject of drug discovery for decades. With the preclinical and clinical phases of CDK inhibitor discovery confronted by drug resistance, low selectivity, and the need for selective inhibitors, and the successful development of CDK inhibitors is challenging. The application of proper patient selection has shown promise in the identification of highly selective CDK inhibitors. Promising results from clinical studies have led to the rapid approval of CDK dual inhibitors by the FDA and EMA; clinical guidelines from the NCCN and ESMO advocate their use in advanced breast cancer in combination with aromatase inhibitors in hormone receptor positive patients. Rapidly evolving data indicate that dual CDK inhibitors may favorably modulate the immune microenvironment and thus may be good partners for checkpoint blockade. Although promising, dual inhibitors will not offer an ultimate cure and tumour cells will engineer a way around them. A key challenge to therapeutic application is determining appropriate biomarkers to identify patients who may benefit most. An area of concern, as with all targeted therapy, is the study of mechanisms of acquired resistance to these drugs. Defining the mechanisms of resistance will be critical for designing future strategies. The inhibition of CDKs thus presents a complicated yet promising line of anticancer therapy. After a brief introduction to the molecular biology of CDKs and CDK inhibition, the chapter will focus on the present status and future prospects of targeting CDKs for cancer therapy, taking lessons from the failures and success stories of clinical trials in CDK inhibition.
Page: 287-314 (28)
Author: Hemant K.S. Yadav, Abrar E. Srouji, Alyazya Mohammed and Manar Dibi
Cancer is considered one of the leading causes of death worldwide. Over the past few decades, researchers have worked reluctantly to discover anti-cancer agents that have saved millions of lives. However, the devastating statistics of increasing mortality due to cancer every year explain the continuous research in this field, to figure out newer agents and approaches for fighting cancer. This chapter will discuss some new drugs discovered which have the ability to effectively target cancer cells including, avelumab, neratinib, niraparib, durvalumab, nivolumab, Erleada and others along with their applications in treatment of various types of cancer like, skin, breast, ovarian, prostate, urothelial etc. Additionally, the chapter will discuss newly adopted strategies in cancer therapy through antibody-drug conjugates and the utilization of some already established non-cancer agents with a potential anti-cancer effect, such as NSAIDs, statins and antidiabetics. Moreover, some new combinations of known anticancer agents have shown additional benefits with significant results that will be further discussed in this chapter as well.
Page: 315-324 (10)
Author: Atta-ur-Rahman and M. Iqbal Choudhary
Frontiers in Anti-Cancer Drug Discovery is a book series devoted to publishing the latest advances in anti-cancer drug design and discovery. In each volume, eminent scientists contribute reviews relevant to all areas of rational drug design and drug discovery including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. The book series should prove to be of interest to all pharmaceutical scientists involved in research in anti-cancer drug design and discovery. The book series is essential reading to all scientists involved in drug design and discovery who wish to keep abreast of rapid and important developments in the field. The ninth volume of the series features chapters covering the following topics: - New research on the therapeutic intervention of cancer and cancer drug delivery - Dabrafenib usage in melanoma therapy - Targeting autophagy in cancer therapy - Pro-apoptotic and anti-telomerase activity of naturally occurring compounds - CDK inhibitors - Oral nanostructure drug delivery for anti-cancer treatment