Frontiers in Anti-Cancer Drug Discovery

Acute Lymphoblastic leukemia (ALL) comprises a subset of different hematologic neoplasms characterized by impaired proliferation of immature lymphoid cells in bone marrow and peripheral blood. Pediatric patients have experienced treatment success with 5- year overall survival rates approaching 90%, whereas ALL adult patients are associated with poorer survival. Therefore, the development of new targeted therapeutic protocols constitutes a primary need. Phosphoinositide 3-kinases (PI3Ks) and their downstream mediators Akt and mammalian target of rapamycin (mTOR) represent the main components of the PI3K/Akt/mTOR signaling network. It is a key regulatory signaling cascade which drives proliferation, survival and drugresistance of cancer cells, and it is frequently up-regulated in the different T- and BALL subtypes. Serious and irreversible late effects from conventional therapy are a growing issue for leukemia survivors, both for adult and pediatric patients. Therefore, the need to develop targeted and personalized therapy protocols for the treatment of leukemias is mandatory. Recent diagnostic tools allow to design therapeutic protocols with increased target specificity towards PI3K/Akt/mTOR axis that represents a critical target for cancer therapy. This chapter will focus on how this pathway could constitute a paradigm for the development of therapeutic strategies and how effective the recent pharmacological Small Molecule Inhibitors (SMIs) can suppress leukemic cell growth.

Among various types of cancers, breast cancer is one of the most frequent and major reasons of cancer death among women worldwide. It has the ability to spread to different organs of the body and develop metastases. Till date, chemotherapy is the most common option for the treatment of breast cancer. However, chemotherapy is not a very successful strategy to cure breast cancer and has decreased the survival rates according to the different breast cancer reports. The inability to deliver a specific drug to the target tissue/cell that causes toxicity to the normal healthy tissue/cell is the primary concern in the chemotherapy. Most of the chemotherapeutic drugs used in conventional chemotherapy have low aqueous solubility and high pre-systemic metabolism; therefore, they are biologically less available to the target location and affect normal healthy tissues/cell as well. Since the last decades, the development of nanoparticle technology has opened a new option in the successful treatment of breast cancer due to the various unique advantages offered by this nanoplatform. Among them, polymeric nanomedicines become the promising choice as the effective drug delivery system and provide great potential in the management of breast cancers as per the outcome of different preclinical studies. Polymeric nanomedicines may exhibit their anticancer efficacy either via passive or active targeting approach. Polymeric nanomedicines can be actively targeted by its surface conjugation to the breast cancerspecific targeting ligands. Active targeting of the nanomedicines has the ability to deliver the specific drug to the target site, therefore, healthy cells remain unaffected by active targeting. Moreover, polymeric nanomedicines have also been exploited in breast cancer treatment through gene therapy. This chapter summarizes the extensive literature of preclinical findings on polymeric nanomedicines exploited in the treatment of breast cancer.

The most frequent cancer related deaths have been associated with lung cancer. The subtypes, Non-Small Cell Lung Cancer (NSCLC) and Small Cell Lung Cancers (SCLC), respond to chemical drugs and radiotherapy. NSCLC (60%) express membrane epidermal growth factor receptor (EGFR). The cell signalling pathway induced by EGFR has been attributed as a key reason for lung cancer progression. There are many FDA approved drugs available for the treatment which primarily includes EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib and gefitinib, or EGFR neutralizing antibody, necitumumab. However, the reports suggest that EGFR can undergo further mutation in tyrosine kinase domain which makes the cells resistant to the ongoing treatment. Alternate signalling pathways may get activated accompanied by epithelial mesenchymal transition and imbalanced microRNAs that contribute towards resistance. Epigenetic changes in lung cancer also offer dynamic targets for cancer therapy. The agents targeting epigenetic changes can be combined with chemotherapy or other-directed therapy so that effective dose and hence toxicity is reduced with enhanced efficacy. Micro-RNAs are the largest class of the gene regulators that regulate the cancer genes. Inhibiting or replacing the cancer-causing miRNAs can be potential targets for cancer treatment. Researchers have also worked on immunotherapy drugs like nivolumab, pembrolizumab and atezolizumab, which reverse the inhibitory mechanism of the immune response. New findings from recent trails provide an optimistic perspective on the progress towards the better treatment of lung cancer.

The delivery of cancer chemotherapeutics has shifted dramatically in the last two decades from parenteral to oral administration. Improved patient compliance, drug tolerability, ease of administration, and potential effectiveness for oral therapy relative to intravenous administration have appeared as the main reasons to use cancer chemotherapeutics through the oral route of administration. However, most of the cancer chemotherapeutics show very poor oral absorption due to the drug’s physicochemical characteristics, stability, and biological barrier (multidrug efflux proteins: P-glycoproteins) present in the GI tract. With advanced research in homolipids and heterolipids as excipients, lipid-based formulations were exploited to enhance the oral efficacy of poorly absorbable cancer chemotherapeutics in recent years. Self-nanoemulsifying drug delivery system (SNEDDS) is the highly developed strategy of emulsion dependent drug delivery systems and relies on the GI fluids for the formation of nanoemulsion inside the in vivo system. The advancement in the field of biocompatible lipid and their derivatives in addition to finding on pharmaceutical excipients such as oil, surfactants, co-surfactants having P-gp modulating potential further extend the interest in SNEDDS for delivery of cancer chemotherapeutics through oral administration. This chapter provides a comprehensive discussion about contemporary advancement in the application of SNEDDS for oral delivery of cancer chemotherapeutics.

Cancer is a multi-factorial disease that necessitates a multi-modality therapeutic approach to accomplish a favorable outcome. Recently, theranostic based systems have been introduced for the diagnosis coupled cancer therapy. The development of targeted novel drug/gene delivery approaches for safe and efficacious treatment of cancer is an emerging arena that includes liposomes, nanoparticles, nanoemulsion, gene therapy, immunosuppressant therapy, herbal bioactive loaded nanocarriers and stimuli sensitive systems (pH, temperature, ultrasound, redox potential, hypoxia and magnetic). Advancements in molecular biology have rendered a wide range of targeting moieties (ligands) and a meticulous understanding of the cancer biology is under extensive exploration for the selection of appropriate targets for cancer treatment. The outcomes of various clinical studies of nanocarriers depict an improvement in the anticancer efficacy and reduction in side effects. This chapter is an assemblage of advances in the novel targeting approaches that enable the cancer prevention, prediction, diagnosis and treatment.