Treatment Landscape of Targeted Therapies in Oncology: Challenges and Opportunities

By Pawan Kumar Maurya

Treatment Landscape of Targeted Therapies in Oncology: Challenges and Opportunities provides up-to-date knowledge on antitumor-targeted therapies and immunotherapy. The book's chapters are written by researchers dynamically working/focusing on cancer treatment. The content is designed to help those who are new to the field (beginners) and various specialized scientists and researchers involved in cancer research. For decades, the hallmark of cancer treatment has been conventional chemotherapy. But with the rapid increase in our understanding of the immune system, more and more small molecules, peptides, recombinant antibodies, vaccines and cellular therapeutic modalities are being applied to manipulate the immune response for cancer treatment.

• Covers basic concepts and updated knowledge of the latest anticancer drugs
• Brings comprehensive understanding of the treatment of cancer in context of immunotherapy and targeted therapy
• Introduces the latest drugs and advancements in the treatment of cancer
• Includes detailed diagrams to give insight to the mechanisms of action

• Language: English
• Publisher: Academic Press
• Release date: Jul 29, 2023
• ISBN: 9780443160356

Book preview

Preface

Pawan Kumar Maurya and Vikas Saini

Cancer is one of the most dreaded diseases of the 20th century and spreading further with continuance and increasing incidence in the 21st century. The situation is so alarming that every fourth person is having a lifetime risk of cancer. It is also one of the leading causes of death, globally. The hallmark of cancer treatment has been conventional chemotherapy. Chemotherapeutic drugs are designed to target not only rapidly dividing cells, such as cancer cells, but also certain normal cells, such as intestinal epithelium. Over the past several years, a new generation of cancer treatment has come to the forefront, that is, targeted cancer therapies. Like conventional chemotherapy, targeted cancer therapies use pharmacological agents that inhibit growth, increase cell death, and restrict the spread of cancer. As the name suggests, targeted therapies interfere with specific proteins involved in tumorigenesis. Rather than using broad base cancer treatments, focusing on specific molecular changes, which are unique to a particular cancer, targeted cancer therapies may be more therapeutically beneficial for many cancer types, including lung, colorectal, breast, lymphoma, and leukemia.

In view of the growing number of targeted drugs for the management of cancer in last two decades, we came up with the idea to explore the possibility of developing a book, which comprehensively address the current and emerging trends in the field of targeted therapies across various cancers types. We discussed, argued, and disagreed until we came up with the thought that a resource book would be a reasonable format, as it could provide sufficient information and literature for instructors to teach the subject, while providing students with ample information to gain better insight about the subject. Finally, we decided to develop a book under the umbrella of Treatment Landscape of Targeted Therapies in Oncology: Challenges and Opportunities by inviting chapters from experts in the field who have relevant research experience and an understanding of the intricacies of the subject.

This book starts with describing the biology of cancer and anticancer targeted drugs developed in last two decades and then providing the most up-to-date knowledge focused on antitumor targeted therapies across different types of cancer: breast cancer, lung cancer, gastric and pancreatic cancer, and so on. This book has been designed in such a way that it will be very helpful to those who are new to the field (beginners) and also to the various other specialized scientists and researchers involved in this developing anticancer drug discovery and development.

This is our maiden effort to produce a book to provide students and instructors a comprehensive understanding of current treatment and future prospects of cancer treatment in the field of targeted therapy We hope that we will get support from the readers of this book. We are always open to criticism, suggestions, and recommendations that can help to improve the content and presentation of the book. Your suggestions and criticisms will give us an opportunity to explore other aspects of anticancer targeted therapy in our future ventures and endeavors.

Chapter 1

Biology of cancer: current insights and perspectives

Sushruta S. Hakkimane¹ and Santosh L. Gaonkar²,    ¹Department of Biotechnology, Manipal Institute of Technology Bengaluru, MAHE, Manipal, Karnataka, India,    ²Department of Chemistry, Manipal Institute of Technology, Manipal Academy of Higher Education, Manipal, Karnataka, India

Abstract

Cancer is the uncontrolled growth of cells that results in the formation of a cell mass called a tumor. The origin of tumors depends on different factors, including environmental causes, metabolic changes, and genetic mutations. Conventional treatment methods, like surgery, chemotherapy, and radiation therapy, fail to provide a complete remission from the disease. The 21st century is the age of exploration for efficient cancer treatment modalities that include targeted therapy, combination treatments, monoclonal antibody-mediated strategies, and immunotherapy. These new approaches are more promising and help to get rid of the recurrence. The individualized treatment methods basically consider the uniqueness of the tumor in terms of surface antigen expression and drug resistance. Several cancer hallmarks have been proposed to elaborate the various pathways used by cancer cells for their survival and development. Since the tumor behavior is too complex for humans, the challenges are piling up one after another.

Keywords

Cancer biology; metastasis; malignant; oncology

Introduction

Cancer is an anomaly in a cell’s internal regulatory systems, which causes the cell to grow and reproduce out of control. Benign or malignant tumors can be distinguished. Since benign tumors have a lower probability to permeate, they are less likely to spread.

A benign tumor may pose a risk to life depending on its occurrence. Most benign malignancies are slow growing with a pushing margin. Cancer’s atiology is caused by a variety of factors, including genetic, hormonal, racial, regional, and environmental influences, as well as age and sex. The modification of DNA sequences brought on by cancer-causing substances results in mutation (carcinogens). Cells in malignant tumors are more aggressive and invasive. Those cells develop the capacity to leave the microscopic environment of their original location and spread to other places. This broadening of tumor cells is termed as metastasis. Hanahan and Weinberg’s descriptions of cancer hallmarks have proven advantageous in our understanding of cancer’s common characteristics and rational drug design. Cancer biology's complicated characteristics are broken down into six main categories in I, and similarly difficult complexity is presented in II. contrastingly challenging complexities. The characteristics of malignant cells according to researchers are less sticky, transmit proteases, angiogenesis, lack of apoptosis, loss of density-dependent inhibition, autocrine growth promotion, loss of contact inhibition, and defective differentiation [1,2].

Normal cells develop a cascade of genetic mutations that enable highly uncontrolled growth and division during the process that results in cancer. The cells may have any kind of mutations like point mutations, promoter and enhancer insertions, chromosomal translocations, and gene amplification. The occurrence of multiple mutations in a single cell is also troublesome. Cancer cells frequently have mutations in proto-oncogenes, which instruct the cell to divide under specific circumstances and at specific times. They accelerate cell division to an unusually high rate when in their mutant condition. Like defective brakes, other genes called tumor suppressors that ordinarily limit excessive cell proliferation typically cease functioning as well. If these genes are mutated, deleted or their functions are lost, it will lead to the development of cancer. The RB gene and p53 gene is a tumor suppressor, meaning that their activation prevents the growth of cancers, playing a crucial function. Oncogenes are another category of factors that have the capacity to induce neoplastic transformation followed by cancer progression when they are overexpressed, amplified, or altered [3].

Angiogenesis is another salient feature of solid malignancies that develops new blood vessels to enhance the supply of resources. It will encourage the cells to metastasize effortlessly and contribute to the overall tumor expansion. The vascular endothelial growth factor is considered to be the key-signaling molecule for the control and mediation of cancer angiogenesis.

Better cancer therapeutic options are progressively becoming possible because of our greater understanding of tumor development and cancer cell biology. The best prospects, however, are in the development of more effective and focused strategies for the targeted elimination of cancer cells. The cell that initiates neoplastic transformation has been discovered, and the mechanisms underlying the invasion of other tissues have been characterized. Today, we define cancer at genetic and epigenomic levels. This information has made it possible to create brand-new medications that target tumor cells alone, educate and manage the immune system to boost its effectiveness, and create ever-greater therapeutic results. But since the battle against cancer is still far from over, scientific research in oncology must remain a top priority on a global scale. The diagnosis and control of the growth or spread of cancer at its initial stage is still proven to be a formidable medical challenge. Similarly, there is a need to lessen disparities in access to medical care and enhance prevention initiatives [4].

A perspective on cancer cell

The metastatic cell must create favprable surroundings within a hostile foreign environment that will allow for its growth and survival. The complex Metastatic cascade is two-important phases: the first stage is the actual spread of a cancer cell from the primary tumor to a distal region, and the second stage is the spread of cancer cells to tissues and organs outside of the site of the original tumor. Later they multiply and develop clinically significant metastases [5]. In that case, individual or small groups of cancer cells must develop the capacity to move and invade to detach from the main tumor and start the metastatic phase [6]. Due to these properties, cells can be broken down and transported via the extracellular matrix of the tissue around them in the direction of the lymphatic and blood vessels, which in turn serve as pathways for the transportation of cells to other distant sites. major cancer’s metastatic pathways varied significantly depending on the patient’s sex and age upon diagnosis. The initial lymph nodes, also known as metinel nodes, that drain visceral, lymphatic, and subcutaneous metastases can be found. Clinical trials should assess the efficacy of metinel node-derived lymphocytes as a potential treatment for disseminated solid cancer. Draining lymph nodes don’t seem to be transitory stopping sites from distal metastases; they seem to be dead ends [7,8]. In fact, the mechanism of hematogenous dissemination appears to be virtually solely responsible for spreading to anatomically distant places [2,9]. Epithelial-to-mesenchymal transition (EMT), a cell-biological mechanism that is crucial to early embryonic morphogenesis, has been identified by developmental biologists over the past three decades. It is a complex process to repress the epithelial nature of tumor cells and transform it into a more mesenchymal morphology. Then, the tumor cells become malignant and start to spread over by achieving mobility. Overall, preventing metastasis effectively requires the use of multiple treatment modalities [10]. Recent discoveries on nonhomogeneity of the individual tumors’ neoplastic cells are an important contribution to this area [11,12]. Many carcinomas and other tumor forms seem to recapitulate the pattern of self-renewing stem cells, progenitor cells, and completely differentiated end-stage cells. Nowadays, cancer stem cells are thought be the origin of tumor and proven its capability to circumvent drug resistance [13]. Since these cells have got an indestructible nature, it will maintain the tumor propagation and make sure its role in the recurrence of cancer disease [14]. Radiation therapy, chemotherapy, and surgery are the three main treatment techniques for cancer. The position of the tumor, histological type, stage and grade, patient health status, etc. are just a few of the variables that determine which modality or combination of modalities is to be used in the treatment [15]. For several reasons, immunotherapy is now recognized as the fourth pillar of cancer treatment [16].

Epidemiology of cancer

Breast, lung, colon/rectum and prostate cancers are the most common incidence of cancers. Human papillomavirus and hepatitis cancer-causing infections, account for major cancer instances in developing or underdeveloped nations. Still, cancer deaths due to Tobacco consumption, high BMI, low intake of vegetables/fruits, alcohol consumption and negligence towards physical activity account for 1/3 of total cancer deaths. Globally, focussed efforts to develop a sustainable framework of measures towards cancer prevention and cancer care for dissemination in transitioning countries would be critical for cancer control. Nowadays, cancer is the second-leading cause of death worldwide, accounting for one in every six fatalities [17]. By 2030, there will be 23.8 million new cases and 13.0 million deaths from cancer, rising from the anticipated 19.3 million cases and 10 million deaths in 2020, according to the International Institute for Research on Cancer [18]. In this regard, it is evident that environmental factors and processed foods play an increasing role in both causing and promoting cancer [19].

Clinical features and diagnosis

The symptoms of a tumor might have been present for a long period, during which their significance was ignored, or many (and sometimes fruitless) investigations were carried out without understanding the necessity for speed. A frequent lack of knowledge about treatment options on the part of the referring physician and a failure to notify patients of the nature of the diagnosis, its ramifications, and treatment options can be added to this delay.

However, practically all specialists face patients with cancer, which has an impact on their profession. Regrettably, many specialists might not be familiar with the fundamentals of cancer medicine. General practitioners are in a vulnerable position when the early symptoms of a malignancy first arise since they treat patients with a variety of, frequently minor ailments. Therefore, oncologists regularly face patients who have cancer that has been present for a long time before diagnosis or who lack a proper diagnosis and have a limited understanding of what treatment can entail. As soon as a patient is diagnosed with cancer, they should be sent for professional advice. Delay in diagnosis and treatment will probably impair the prognosis.

Current and emerging treatment strategies

A growing number of tools are available to clinicians in the treatment of cancer, including cancer therapy. However, cancer is a formidable foe in this conflict, and current therapies—which often include surgery, chemotherapy, and radiotherapy—rarely suffice to cure patients of their malignancy. Cancer cells can grow resistant to the treatments directed at them, thus reducing this drug resistance is a major research topic. To get better results and cures, hormone therapy, immunotherapy, adjuvant therapy, targeted-growth signal inhibition, and apoptosis-inducing medicines have started to be explored. The most advanced techniques that involve nanotechnology—RNA expression and profiling and CRISPR—have been employed for the design of more efficient drugs and therapeutic strategies [20]. In addition, chemotherapeutic drugs can be used with oncolytic viruses to eradicate cancer cells [21].

Modern challenges in cancer therapy

Important challenges are still ongoing in both fields of cancer therapy. Single molecular aberrations or cancer pathways have been the focus of successful treatment interventions that have marginally improved survival in several cancers. To improve patient treatment outcomes, several obstacles must be overcome because this strategy for treating cancer is still reductionist.

It is unknown if research on cell-autonomous metabolic reprogramming can help find the most effective treatment targets. Targeting glycolysis has had only modest success. More acceptable doses in recent trials have been unsatisfactory because they still caused hypoglycemia symptoms while causing tumor responses when patients were exposed to high amounts of 2-deoxyglucose [22]. Direct attempts to combat the Warburg effect have also had mixed results.

Lactate dehydrogenase (LDH) dependence has been shown to be pharmacologically and genetically dependent [23–25], leading to the development of LDHA inhibitors [26]. None of these substances, however, advanced to clinical trials, which suggests either intolerable toxicity, insufficient drug exposure, or a deficiency in LDHA. In addition, the use of LDHA as a target in treatment and diagnosis has given better results and future research focuses on the use of LDHA inhibitors in combination with molecularly targeted medications and immunotherapy is necessary for addition to sensitizing conventional cytotoxic chemotherapeutics [27].

The evidence gathered over the past few years demonstrates dichloroacetate ability to overcome radio- and chemo-resistance in a variety of cancer types and allows for the speculation of additional cellular targets that could account for its capacity to eradicate cancer cells [28]. By focusing on oncometabolites to help patients with IDH-mutated malignancies, D-2-HG-mediated alternations present challenges for the treatment of cancer and prospective therapeutic possibilities.

Dichloroacetate, a pyruvate dehydrogenase kinase inhibitor, causes metabolic changes in human malignancies [29], yet there are few efficacy data available. Pyruvate dehydrogenase is active and required by some malignancies, according to recent research [30,31], which dampens hopes that help to activate the enzyme will be therapeutically beneficial. The reversal of 2HG-mediated reprogramming in IDH mutant tumors is one achievement in tackling cancer metabolism. Elevated 2HG-induced vulnerabilities may be exploited as a novel therapeutic strategy [28,32].

In general, the challenges of cancer treatment can be met at different levels. Sometimes the research will fail to identify metabolic targets, or it may have difficulty finding responsible genetic alterations at the tumor site. Because tumor cells have acquired drug resistance, it is critical to target the drug resistance mechanism as well.

Metabolic therapy and metabolic targets in cancer

The metabolic heterogeneity inside and between cancers is substantially smaller than the genetic heterogeneity of tumors, making targeting tumor metabolism an appealing anticancer therapy. Clinical prospects with the ability to choose patients based on tumor genetics are presented by transforming mutations in metabolic enzymes. Most metabolic alterations, however, are not caused by mutations in metabolic enzymes, and similarly, in concern of IDH mutations, a persistent condition of mutant enzyme dependency may not necessarily exist [32]. Thus, a key treatment issue is how to choose individuals for medications that target metabolic enzymes.

One strategy has been to scan cell-line panels to find malignancies that are genetically sensitive and then to test these theories in animal models, which is based on the success of creating protein kinase inhibitors. However, the use of different nutrients in tumors and culture shows that it may be possible to uncover activities that are neutral in vivo when using cell lines to detect sensitive tumors. On the other hand, facilitating routes in vivo might not be as significant in culture. Numerous cancer types have been found to require glutamine metabolism [33], however, this characteristic depends on both the tissue of origin and heredity [34].

A combination of hereditary and nongenetic variables can also affect the auxotrophy of various malignancies for specific amino acids. However, asparaginase therapy for acute lymphoblastic leukemia is beneficial even when asparagine synthase is produced, indicating that additional mechanisms strengthen the requirement for exogenous asparagine. In contrast, several studies in recent years have found that asparagine synthetase (ASNS) is overexpressed in some cancer types, promoting cell proliferation, chemoresistance, and metastatic behavior. They focus on the impact of ASNS activity in the biology of regular and malignant tissues, with an emphasis on how ASN interchange between cancer cells and the tumor microenvironment. The function of ASNS may vary by cancer type and should be assessed individually. Because of this, it is crucial to find precise and powerful inhibitors of ASNS expression and activity in human malignancies, and this search has been ongoing for many years [35,36]. A few mutated metabolic enzymes are also having a direct impact on malignancy. These enzymes, therefore, seem to act as oncogenes and tumor suppressors, making them appealing targets for therapeutic intervention [37,38].

Genetics influences sensitivity to some enabling metabolic targets, like passenger deletion of enzymes that inhibit metabolic compensation in tumors. This lessens metabolic redundancy and makes it possible to target Enolase ENO2 therapeutically [39–41]. It is also possible to target alterations in gene expression that result in auxotrophies for amino acids; L-asparaginase serves as an example of this. Patients with malignancies that lack ASS1 are being investigated for arginine-depleting medications [42]. Dietary serine restriction may be effective in treating some p53 mutant tumors [43].

Cancer drug resistance

Cancer cells will develop drug resistance through a variety of mechanisms and resistance to anticancer medications is a complicated process. Traditional treatments for cancer could evolve resistance, and the occurrence of such drug-resistant tumors is rising, necessitating interventions focused on and advanced therapy development. Drug inactivation, drug efflux, drug target modification, DNA damage repair, EMT, epigenetic effects, inherent cell heterogeneity, or any of these combination mechanisms can have an overall impact on cancer treatment drug resistance. Treatment of patients with drug combinations may be one strategy to prevent or delay the emergence of resistance. It could be more efficacious than using the single drug and prevent the emergence of drug