Frontiers in Anti-Cancer Drug Discovery

Hepatoblastoma is the third most common pediatric tumor of the abdomen with an incidence of about 1.2-1.5 cases/million population/year. It has been associated with various genetic conditions, such as familial adenomatous polyposis, Beckwith- Wiedemann syndrome and Edwards syndrome, while genetic mutations of the Wnt signaling pathway are also frequently seen. The different staging systems and treatment approaches of the four hepatoblastoma study groups, International childhood liver tumors strategy group, Children’s Oncology Group, German Society for Pediatric Oncology, and Japanese Study Group for Pediatric Liver Tumors, led to different outcomes among the various trials published over the years. Some groups tended to follow a protocol of an upfront surgical resection, while others suggested neoadjuvant chemotherapy to all patients. Now these groups try to come on the same page by initiating an international collaborative attempt to pool previously published data, as well as to classify future patients into risk-stratified groups that would determine treatment options and facilitate improved survival outcomes. The aim of this chapter is to review the general characteristics of hepatoblastoma, the various treatments implemented over the last years, as well as the challenges in management that its rarity and discrepancies among the study groups pose.

Cancer has become a global pandemic that accounts for almost 13% more deaths than any other infectious diseases. According to the World Health Organization (WHO), projections of cancer prevalence is expected to raise to 21.7 million cases and 13 million deaths by 2030. Over the last 10 years, considerable improvements have been achieved in the management of cancer, and yet the disease remains incurable. There is an urgent need to develop therapeutic agents with novel drug combinations to achieve better efficacy, and reduce the possibility of relapse and drug resistance.

Cancer progression, development of metastases represents the major characteristic feature for solid tumours in the presence of hypoxia. Under hypoxic conditions, cancer cells consume glucose that is metabolized to lactate, and then exported into the extracellular milieu, contributing to the acidic microenvironment. In this context, monocarboxylate transporters (MCTs) will play a significant role in maintaining the hyper-glycolytic acid resistant phenotype of cancer, allowing the maintenance of the high glycolytic rates by performing lactate efflux, and pH regulation by the cotransport of protons. Hence, MCTs constitute attractive adjuvant targets for cancer therapy.

In this chapter, we review cancer biology from the perspective of the lactate shuttle concept which mainly focuses on the development of MCT inhibitors and highlights current and potential future therapeutic approaches that supports the notion of targeting lactate metabolism with novel anticancer agents.

The hallmark features of cancer emphasize essential biological characteristics associated with malignant transformation. Anti-cancer drug discovery is a strenuous task, requiring a number of pre-clinical and clinical investigations. Preclinical investigations offer a foundation for anti-cancer drug discovery. A number of cell based in-vitro assays have been introduced to investigate each major hallmark feature of cancer. Selection of the most suitable in-vitro assay for pre-clinical investigations mainly depends on the researcher’s objective(s) to be investigated. A wide range of cell based in-vitro anti-proliferative assays/techniques have been developed based on different assay principles and chemistries to evaluate the effects of testing agent (s) on cancer cell proliferation. In this chapter, we have outlined commonly utilized cell based anti-proliferative assays in pre-clinical anti-cancer drug discovery approaches.

A solid and useful connection exists among eating regimen and malignancy. An inaccurate diet may increase the incidence of all types of cancer from 10% to 70%. Polyphenols are found in more than 700 foods, particularly foods grown on the ground (such as herbs), flavorings, and even nuts and cocoa items. Many food items considered superfoods; top superfoods include blueberries, apricots, grapes, olives and olive oil, artichoke, herbs (e.g., oregano, peppermint, and cloves), nuts and seeds (e.g., walnuts, almonds and flaxseeds), and green tea. Polyphenolic compounds can lead to epigenetic modification of chromatin and modulation of membrane organization; they can also interfere with interaction of the various macromolecules and regulation of the telomerase activity. They play crucial roles in modulating the multiple cellular pathways individually. Pure polyphenolic agents may be used as therapeutic agents, in combination with conventional therapy for improved cancer treatment. This chapter summarizes the anticancer efficacy of major polyphenolic compounds and discusses the potential mechanisms of action based on epidemiological studies.

Brain tumors are most aggressive lethal types of cancer and have been reported to have poor prognosis. Patients diagnosed with glioblastoma multiforme (GBM) have an aggressive, tough and resistant brain tumor with average survival 12 to 16 months. The most common age for diagnosis of GBM is reported to be in between 45 and 70 years. GBM arises from glial cells which are glue like supportive cells of the brain that help to maintain and protect the neurons of central and peripheral nervous system from any damage. GBM is usually treated with surgery and radiation followed by chemotherapy where temozolomide (TMZ) is a part of therapy. TMZ is an alkaline agent that destroys the glioblastoma cells by forming O6-methylgunine in DNA. TMZ is an anticancer drug popularly used sometimes along with ionizing radiation. However, one of the downsides of chemotherapy is the development of resistance against the drug which results in the failure of the treatment and hence poor prognosis. The alternate treatment strategies are being explored to prolong the survival of GBM. The treatment of GBM by using HDACi (histone deacetylase inhibitors), MGMT (O6-methylguanine DNA methyltransferase) inhibitors, beta blockers, statins, antimetabolites, and some phytotherapeutics in synergistic combinations may be beneficial for outcome. A number of drugs are being investigated in synergistic combination and will offer a substantial survival advantage in GBM patients. The present chapter discusses the synergistic combinations of mainly TMZ with various other anti-cancer or FDA approved drugs for other indications that can enhance different molecular mechanisms, increase cell death, reduce drug resistance or decrease the drug toxicity in glioblastomas.

The application of nanomaterials in biomedicine is a very active field of research, as it has the potential for developing several innovations in health care, diagnosis, medical imaging and therapy. In particular, the use of nanostructured materials for drug formulations is drawing the attention of pharmaceutical companies and research groups around the world. The development of new systems for controlled drug transportation and delivery is a very complex multidisciplinary field since they must possess unique physical and chemical features to improve the stability of the active pharmaceutical ingredient, to enhance drug bioavailability and delivery efficiency, as well as to control the drug clearance rate. Nanomaterials present unique physical properties that offer several advantages over traditional carrier systems. There are several systems that can be selected for a specific formulation, depending on the administration route, such as carbon nanostructures (e.g., graphene, graphene oxide and carbon nanotubes), nanoliposomes, micelles, dendrimers, polymeric and inorganic nanoparticles (e.g., metallic, metal oxides and composites), among several others. All the aforementioned systems will require intensive research to thoroughly understand their safety and long-term effects in order for them to be included in health products in the future. This chapter reviews the most recent progress on the development of mesoporous nanocarriers for controlled transport and delivery of anti-cancer drugs. First, some fundamental ideas are discussed on the actual benefits and risks of using nanomaterials in pharmaceutical formulations, compared with current existing technologies. Some of the most representative mesoporous materials used to develop efficient nanocarriers are presented. Their physical and chemical properties are introduced to better understand their advantages in terms of the design of efficient systems for the controlled delivery and release of anti-cancer drugs. Moreover, the design of novel anti-cancer drug transport and delivery systems that harness the unique characteristics of mesoporous nanomaterials is addressed. Finally, some of the potential risks associated with the biomedical use of nanostructured materials, related to their diverse chemical compositions, physical properties and technological applications, are examined along with proposed ways to minimize their potential health and environmental impact.

Breast cancer is one of the major reasons for mortality and trauma amongst women. Therapy for breast cancer has various options such as, chemotherapy, hormone therapy, gene therapy, immunotherapy, and radiation therapy. Chemotherapy is the choice in most cases but is often associated with side/adverse effects. These side/adverse effects can be eliminated by delivering the drug to the target site. With the help of nanotechnology and drug delivery through a suitable carrier, targeting has become achievable. Targeting includes both, the active as well as the passive approach. Passive targeting is based on the accumulation of the drug over tumor tissues whereas active targeting is done by means of an interaction with the receptor/antigen and the targeting moiety. Nowadays, the focus is on the active targeting of drugs in which an approach to target the drug directly to the diseased cells is taken. The approaches can be broadly classified mainly into antigen-antibody, aptamers, ligand-receptors and lectin-carbohydrate based, respectively. Every targeting strategy is based on one basic concept, i.e. an overexpression of a biomarker on a specific diseased cell type. Hence, a suitable moiety is utilized to carry out the active targeting of drugs. Apart from chemotherapeutic agents, hormonal drugs, gene silencing molecules can also be successfully delivered through nanotechnology. Some of the nano based medicines are already in the market and there is a constant enhancement in the success of the systems. Some are in the trial phase and some approaches have been patented. However, the translational challenge yet exists and there is a need to overcome it. Thus, this chapter discusses the various delivery systems, different materials and various approaches for the active targeting of the drug, recent clinical trials, challenges and some recent patents.