Frontiers in Anti-Cancer Drug Discovery

Malignant pleural mesothelioma (MPM) is a cancer with aggressive nature and poor prognosis (the median survival ranges from 9-18 months). The worldwide incidence of this disease is increasing, with 2180 estimated new cases diagnosed in the United States in 2013. Despite the apparent benefits offered by the multimodal approach (a combination of surgery, chemotherapy -cisplatin/ pemetrexed- and radiotherapy), survival remains poor. As a consequence, multiple therapies aiming to improve the evolution of the disease are under investigation. In this chapter, we will summarize some of the new preclinical and early clinical developments in the treatment of MPM, which include mesothelin specific antibody and toxin therapies, gene therapy, interleukin-4 (IL-4) receptor toxins and dendritic cell vaccines, among others.

Colorectal cancer (CRC) is the second most commonly diagnosed cancer and the third leading cause of cancer related death in the world. Epidemiological studies show that CRC incidence and mortality vary substantially across different regions of the world. CRC is a multifactorial disease process, in which may intervene familial and hereditary factors, as well as age, environmental causes, lifestyle-related risk factors, namely diet and inflammatory conditions of the digestive tract. Several genetic alterations have been associated to the process of colon carcinogenesis, namely epidermal growth factor receptor (EGFR) activation, BRAF and KRAS mutations among others.

Many options for CRC treatment are available, including surgery, chemotherapy, and radiation. Herein, we will describe the main classical drugs used in CRC chemotherapy, such as 5-Fluoracil, Leucovorin, Irinotecan, and Oxaliplatin. Recent anti-CRC therapies are now targeting specifically signaling pathways implicated in colorectal carcinogenesis, such as EGFR (Cetuximab, Matuzumab, Erlotinib, Panitumumab), which appears highly overexpressed in most CRC patient cases. However, this approach is limited by resistance conferred by the activation of mutations in EGFR downstream signaling pathways. As a result, an increasing number of specific components of these pathways have been targeted in order to overcome the resistance to conventional EGFR-targeted therapies. Despite the recent advances, conventional chemotherapy remains unable to improve the prognosis of advanced or recurrent CRC.

In colorectal environment, there is a symbiotic relationship between intestinal cells and bacteria from the diet. Indeed, colonocytes metabolize short-chain fatty acids (SCFA), byproducts of anaerobic bacterial fermentation of dietary fiber. These SCFAs play a significant role in maintaining the normal physiological functions of the colon mucosa, but they also have strong anti-tumorigenic properties, such as reduction of cancer cell proliferation and differentiation and stimulation of apoptosis in CRC cells. Here we discuss the exploitation of anti-apoptotic features of SCFA in the development of new prevention and therapeutic approaches.

Changes in cellular metabolism are a crucial hallmark of cancer and CRCs were shown to present a glycolytic phenotype even in the presence of oxygen, phenomenon commonly designated as the ‘Warburg effect’. We will also discuss the use of metabolic inhibitors as new therapeutic adjuvants per se or in combination with other therapies.

To reduce off-target associated adverse effects and achieve targeted drug delivery in cancer therapy, nanomedicine is emerging as a promising strategy. The transport of classical drugs by nanoparticles has shown great promise in improving drug distribution and bioavailability, increasing the anticancer molecules concentration at the cancer tissue, providing optimal drug delivery, and minimizing drug toxicity. Additionally, targeting CRC cells may be improved by incorporating ligands for cancer-specific surface receptors such as EGFR, bringing new opportunities in the treatment of patients with CRC.

Pancreatic cancer has been increasingly diagnosed in the recent decades. Although the cornerstone treatment for pancreatic cancer is surgery, unfortunately, only 15-20% has a resectable disease at the time of initial diagnosis. Owing to the majority of patients having either locally advanced diseases or metastases, chemotherapy plays an important role in the management of pancreatic cancer. Because conventional chemotherapy has its limitations in the management of pancreatic cancer, recently developed molecular targeted therapy has emerged as an important modality of treatment of the disease. Drugs targeting growth factors such as epidermal growth factor and anti-angiogenesis have been studied and have promising results. Some of these drugs such as erlotinib have been already approved for the treatment of pancreatic cancer. Newer drugs such as those targeting hedgehog signaling pathway are now being tested. In this chapter, we will comprehensively review the current and also the latest development of anti-pancreatic cancer drugs.

Hormone receptor (HR) positive breast cancers (BCs) represent the vast majority of BCs with estrogen receptor (ER)+ and/or progesterone receptor+ BCs comprising the vast majority of all cases. Tamoxifen (Tx) is a selective estrogen receptor modulator that is mainly indicated for premenopausal women with HR+ BCs (as monotherapy), resulting in a significant reduction of BC mortality. The "classical" duration of Tx therapy was 5 years. However, the results of recent trials indicate that 10 years of adjuvant Tx reduces further BC mortality. In premenopausal women, available data suggest that ovarian suppression provides no additional benefits for women treated with adjuvant Tx with the exception of women who are at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remain premenopausal. Aromatase inhibitors (AIs)-anastrozole, exemestane and letrozole-have become a useful adjuvant therapy in the management of postmenopausal patients with HR+ BCs, which proved superior to Tx. Recent guidelines recommend a 5-year course of AIs, administered as initial monotherapy or after Tx, for postmenopausal women with HR+ early BCs. In premenopausal women, it is not appropriate to administer AIs as monotherapy because the low levels of estrogen could stimulate hypothalamos-pituitary axis which could trigger the ovaries for estrogen production. Taking into account the superiority of AIs to Tx, a logical hypothesis was to use AIs in premenopausal women after inducing a menopausal status with GnRH analogues. However, the use of AIs is not generalized in premenopausal women (where Tx is beneficial) but only in high risk cases (women ≤35 years old, and/or large tumor, high tumor grade, involved lymph nodes, lymphovascular invasion, high recurrence score), where exemestane proved beneficial.

Liver cancer is an aggressive malignancy developed in the liver. Hepatocellular carcinoma (HCC) is the predominant form of liver cancer worldwide. The prognosis of HCC patients remains poor even with the evolving development on technologies for disease diagnosis, prognosis and treatment. New methods to improve the management of HCC patients should be implemented. Cell cycle deregulation is one key mechanism leading to HCC. Cyclin E is a cell cycle molecule regulating G1 to S phase transition of the cell cycle. The prominent cell cycle regulating function of cyclin E has signified its involvement in HCC when its activity is deregulated. This chapter summarizes the current research on cyclin E in HCC and with a special focus on its underlying, well-studied downstream mechanism involving retinoblastoma-E2F transcriptional factor network. Lastly, research on the potential use of cyclin E for HCC prognosis and treatment is also highlighted and discussed.