Frontiers in Clinical Drug Research - Anti-Cancer Agents

Regardless of the diverse modes of treatment, the prognosis and clinical response of AML (Acute myeloid leukemia) remain low as the conventional modes of treatment, including cytarabine and anthracycline have their limitations. Moreover, chemotherapy-induced cytotoxicity triggers the remission, thus most of AML patients succumb to relapse. The monotherapy is also not helping much due to the rapid growth of AML, while an insufficient period of time is a major barrier in immunotherapy. Therefore, the current focus has been on combination therapy, with different agents, possibly because chemotherapy for AML is associated with infection, inflammation and could be rather toxic when combined with immunotherapy. Thus, there is the utmost need for developing a new approach and treatment for AML. Recent therapies focus on various novel signaling pathways and proteins that promote the survival of cancer cells in AML patients. This single or combinatorial approach may be more effective with less harmful effects. In this context, here we are discussing the role of PI3K/AKT/mTOR pathway in the survival of malignant cells as a potential target to combat relapse in AML patients. Accordingly, the therapeutic agents with a new class of inhibitors for plausible approaches to treat the patients with relapsed or refractory AML diseases could be advocated.

Prostate Cancer (PCa) is a major global health burden with alarming epidemiological indices. Research advances in this area have revealed complex molecular aspects associated with the disease, thus necessitating the novel development of diagnostic methods and therapeutic strategies. The main molecular target is the androgen receptor (AR), which is involved in both normal development and malignant transformation. However, many patients become resistant to conventional treatments, and the disease progresses to a castration-resistant stage (CRPC) in which tumor aggressiveness is driven by a constitutive activation of AR signaling. Tremendous effort has been made for elucidating CRPC and chemoresistance. In fact, multiple signaling pathways are related to the insurgence and maintenance of CRPC, highlighting the need for continuously updating such a complex scenario. Different drugs have been tested and used for CRPC treatment, facing unfavorable heterogeneity and leading to substantial morbidity and mortality. Thus, the clinical impact of advanced PCa with poorer outcomes still underscores the need for new compounds. The discovery and current use of natural products has given way to promising possibilities, offering alternative tools that aim to control the disease and to better manage patients. These natural products are versatile and effective molecules with different mechanisms of action and structures. In the present chapter, we explore the challenges of PCa and describe recent scientific contributions in this field, with special attention devoted to CRPC. We also discuss and suggest natural products as potential novel anti-tumor agents to overcome clinical limits and to treat and cure CRPC patients.

Human genome sequencing has revealed the complex nature of the human proteome. Researchers have been focused on mapping the proteome to find the right target for drug design. Inhibition of target proteins may be complemented by redundant forms of the proteins in the pathogenesis of diseases. Therefore, it is important to determine key proteins and their coordinating and/or cooperating partner proteins in protein pathways to design innovative chemotherapeutics. Computational and experimental studies indicated that approximately 200.000 protein-protein interactions (PPIs) have been predicted, with only about 8% identified in humans. PPIs play key roles in many important cellular processes, and especially their up-regulation is closely associated with each step of the tumurogenesis in cancer cells. Therefore, the identification of protein interactions helps researchers to design drugs for target specific cancer treatment. To understand the relations between tumorigenesis and p53- MDM2, c-MYC-MAX, Bcl-2/Bcl-xL, Hsp90-Hsp70, β-catenin-TCF4, and Menin- MLL interactions are an important approach to design specific chemotherapeutics for the treatment of individuals with cancer. This work focuses on key protein interactions on protein signaling pathways and designed inhibitors at these specific junctions in the literature.

As per the latest data of the International Agency for Research on Cancer, more than 8 million individuals die annually owing to the exacerbation of a given neoplasm, and the total number of annual deaths due to hepatocellular carcinoma (HCC) is 0.78 million, the second-highest of all cancer-related deaths. HCC has a very poor prognosis, reflected by the fact that the incidence-to-mortality ratio of HCC has been estimated to be more than 90%. Liver cancer is generally diagnosed only in the advanced clinical stage because HCC tends to be clinically silent during the early stages. With regard to HCC management, transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC), as well as molecularly targeted agents such as sorafenib and lenvatinib, have shown promising benefits for advanced HCC. However, even though the Barcelona Clinic Liver Cancer staging system has been widely accepted, controversies still exist regarding the best choice for the management of HCC in individual cases. In this chapter, we infer that HAIC treatment is not inferior to molecularly targeted therapies for the treatment of advanced HCC—particularly in case of intravascular invasion in both compensated and decompensated cirrhotic patients. Furthermore, the rate of adverse events leading to discontinuation of antitumor treatment appears relatively low. Given the hepatic function reserve preservation afforded by HAIC chemotherapy, we suggest that HAIC should be considered as an alternative strategy even for advanced-HCC patients with decompensated cirrhosis, who do not respond to TACE.

Cancer is a serious global health concern as it accounts for about 9.6 million deaths worldwide. Despite striking breakthroughs made in understanding, prevention, and treatment of cancer, the mortality rate is still high and no permanent cure has been found. The major concern is the lack of effective therapies against advanced metastasis. Thus, there is a dire need to implement new treatment approaches to combat this dreadful disease. Cancer stem cells (CSCs), being critical players of tumors can be the potential target for therapy. Currently, cancer stem cell therapy is gaining much attention from researchers because of its ability to target the CSCs, which are responsible for tumor initiation, progression, metastasis, therapeutic resistance, and recurrence. While most conventional treatment strategies target fast-growing tumor cells, CSCs may remain in the latent stage for extended periods thereby escaping the traditional therapies and leading to treatment resistance. Hence, specific targeting of the tumor-initiating cells has become the heart of cancer research, aiming at the complete elimination of malignancies. Major strategies against CSCs include targeting surface CSC biomarkers, blockage of self-renewal signaling pathways (Wnt, Nanog, Hippo/YAP, Notch, PTEN, Hedgehog, and/or STAT3), genetic targeting of CSCs, cell therapy, RNA interference utilizing miRNAs. Based on this concept, the present chapter summarizes the current strategies and the lead molecules which have found their route to preclinical and clinical studies. Since the evolution of clinical trials targeting CSCs holds a sanguine promise of affecting cancer medicine. This chapter will further throw light on rapid advancement made in this field, shortcomings faced in targeting CSCs, and several critical issues that are yet to be resolved.