Current Cancer Therapy Reviews - Volume 15, Issue 2, 2019

Testicular germ cell tumors (TGCTs) are unique to that of most other solid tumors because they are highly curable in the metastatic setting. While the use of cisplatin-based chemotherapy continues to drive cure in this patient population, important improvements in the delivery of therapy, creation of risk-adjusted treatment paradigms, and salvage-therapy options have further enhanced survival as well. The future holds promise for a more multidisciplinary approach to care, through advancements in biochemical markers and a better understanding of how surgical and radiotherapy approaches can integrate into our existing management strategies.

A growing body of research evidence supports the benefit of exercise for cancer survivors both during and after cancer treatment. The purpose of this paper is to provide an update on our previously published review in 2006 on the state of the evidence supporting exercise for survivors of cancer as well as guidelines for integrating exercise programming in the cancer clinical setting. First, we provide a brief overview on the benefits of exercise as well as preliminary evidence supporting the implementation of community-based exercise programs. Second, we summarize the principles and goals of exercise, and the identified barriers to exercise among cancer survivors. Finally, we propose an interdisciplinary model of care for integrating exercise programming into clinical care including guidelines for medical and pre-exercise screening, exercise testing and programming considerations.

Metastatic melanoma treatment has dramatically changed in the last few years, having a breakthrough with the introduction of targeted agents and immunotherapy. PD-1/PD-L1 pathway is one of the physiologic mechanisms of peripheral immune tolerance, but it also represents a mechanism of tumor immune escape. PD-1/PD-L1 inhibitors represent new immune-checkpoint drugs currently used in metastatic melanoma treatment. Resistance to PD-1/PD-L1 axis blockade, which is the main cause of therapeutic failure during therapeutic use of these drugs, could be linked to several mechanism of immune escape. In fact, other inhibitory receptor such as CTLA-4, LAG-3, TIM-3 and TIGIT might be co-expressed on T cells, deleting the effect of anti-PD-1/PD-L1; overexpression of the enzyme IDO could cause immunosuppression through the depletion of tryptophan in the tumor microenvironment; defective c ostimulation (through reduced activity of 4-1BB and OX40 receptors) could result in T-cell energy. Combination of anti-PD-1/PD-L1 with drugs targeting inhibitory or costimulatory receptors, intracellular pathways, enzymes or neoangiogenesis could be a possible strategy to overcome resistance to single PD-1/PD-L1 blockade. Clinical trials evaluating combination therapies have already showed interesting results, although most of them are still on going.

At the present time, cancer is one of the most lethal diseases worldwide. There are various factors involved in the development of cancer, including genetic factors, lifestyle, nutrition, and so on. Recent studies have shown that epigenetic factors have a critical role in the initiation and development of tumors. The histone post-translational modifications (PTMs) such as acetylation, methylation, phosphorylation, and other PTMs are important mechanisms that regulate the status of chromatin structure and this regulation leads to the control of gene expression. The histone acetylation is conducted by histone acetyltransferase enzymes (HATs), which are involved in transferring an acetyl group to conserved lysine amino acids of histones and consequently increase gene expression. On the basis of similarity in catalytic domains of HATs, these enzymes are divided into different groups such as families of GNAT, MYST, P300/CBP, SRC/P160, and so on. These enzymes have effective roles in apoptosis, signaling pathways, metastasis, cell cycle, DNA repair and other related mechanisms deregulated in cancer. Abnormal activation of HATs leads to uncontrolled amplification of cells and incidence of malignancy signs. This indicates that HAT might be an important target for effective cancer treatments, and hence there would be a need for further studies and designing of therapeutic drugs on this basis. In this study, we have reviewed the important roles of HATs in different human malignancies.

The mevalonate pathway (also known as the cholesterol biosynthesis pathway) plays a crucial metabolic role in normal cell function as well as in the pathological environment. It leads to the synthesis of sterol and non-sterol isoprenoid biomolecules which subserve a variety of cellular functions. It is known to be deregulated in many disease processes. Statins and bisphosphonates are prominent inhibitors of the mevalonate pathway. They inhibit cell proliferation and activate apoptotic signalling and suppress tumour growth. Statins subdue metastatic spread of tumours by virtue of their ability to suppress invasion and angiogenesis. The induction of autophagy is another feature of statin effects that could contribute to the suppression of metastasis. Herein highlighted are the major signalling systems that statins engage to generate these biological effects. Statins can constrain tumour growth by influencing the expression and function of growth factor and receptor systems. They may suppress epithelial mesenchymal transition with resultant inhibition of cell survival signalling, together with the inhibition of cancer stem cell generation, and their maintenance and expansion. They can suppress ER (oestrogen receptor)-α in breast cancer cells. Statins have been implicated in the activation of the serine/threonine protein kinase AMPK (5' adenosine monophosphate-activated protein) leading to the suppression of cell proliferation. Both statins and bisphosphonates can suppress angiogenic signalling by HIF (hypoxia- inducible factor)-1/eNOS (endothelial nitric oxide synthase) and VEGF (vascular endothelial growth factor)/VEGFR (VEGF receptor). Statins have been linked with improvements in disease prognosis. Also attributed to them is the ability of cancer prevention and reduction of risk of some forms of cancer. The wide spectrum of cancer associated events which these mevalonate inhibitors appear to influence would suggest a conceivable role for them in cancer management. However, much deliberation is warranted in the design and planning of clinical trials, their scope and definition of endpoints, modes risk assessment and the accrual of benefits.

Background: Turcot’s syndrome (TS) is a rare disease with known incidence of about 1-2 cases per year. It is, however, linked to high mortality due to the brain cancer. And because of this, we propose recommendations, aimed at preventing the mortality of the patients and to minimize the risk of undiagnosed Turcot’s syndrome. Methods: The authors collected the worldwide published data on TS, from the year of its definition till 2018, all of which was published on the search engines, such as Medline, Medknow, Cohraine and Wiley. Results: We included 97 patients, 57 from which are females and 40 males with median age of 22 years. The most common type of cancer is medulloblastoma, followed by glioblastoma and astrocytoma. We further divided the patients into two categories based on the first symptom of the disease and we made an algorithm of approaching these patients. Conclusion: TS is a disease that affects mostly members of families with multiple genetic mutations and types of cancers. And because of the unknown mechanisms of inheritance, it is useful to establish guidelines for the approach of those patients, in order to minimize the high mortality rate.

Background: Lung cancer is one of the main causes of cancer mortality in both men and women. Up to 80% of lung cancers are Non-small-cell lung cancer (NSCLC). With regards to the role of serotonin, as an autocrine growth factor for small-cell lung cancer cells and gammaaminobutyric acid (GABA) and its receptors as a regulator in many types of cancers; the current study was conducted to investigate the expression of serotonin and GABA gene receptors in lung cancer patients. Methods: Relative gene expression of two 5-hydroxytryptamine subtypes (5HTR2A and 5-HTR3A) and GABAB receptor was measured by quantitative polymerase chain reaction in peripheral blood mononuclear cell (PBMC) from 30 NSCLC patients visited in Imam Khomeini hospital, Tehran and 30 healthy controls. Results: Our results demonstrated that the expression of 5HTR3A, 5HTR2A and GABAB R genes was significantly higher in patients compared to the healthy individuals. Conclusion: According to our findings, 5-HT and GABA may be involved in the regulation of tumorigenesis via their receptors, thus playing an important role in lung cancer.

Background: Cancer is one of the major causes of the death and affects people of all ages throughout the world. The drugs that are currently available to treat cancer have many side effects. Hence, there is considerable scientific interest in the continuing discovery of new anticancer agents from natural sources. The aim of this study was to prepare and characterize nanoparticles combining Indigofera intricata crude alcoholic extract and chitosan and to evaluate the anticancer cell proliferative activity for both extract and nanoparticles. Methods: Dried alcoholic extract was prepared and characterized for its phenolic and flavonoid contents. Chitosan extract nanoparticles was prepared by ionic gelation method and characterized by thin layer chromatography (TLC), Fourier-transform infrared spectroscopy (FTIR), particle size and zeta-potential analysis. The anticancer cell proliferative activities of both plant extract and nanoparticles at different concentrations were evaluated using breast cancer cell line (MCF 7). Results: The alcoholic extract showed high contents from both phenolic and flavonoid constituents (15 % and 22 % respectively). The interaction of polyphenolic compounds of the extract with chitosan was confirmed by the TLC and FTIR results. The particle size and zeta-potential of nanoparticles found to be 400.6nm ± 101.8 nm and +42.1 mV ± 9.27 mV respectively. The plant extract showed the lowest cell viability of 45.21% ± 4.8% at the highest dose (250 mg) tested in this investigation. Almost 500-fold reduction (from 250 mg to 0.5 mg) in the extract concentration required to achieve same anticancer cell proliferative activity when formulated as nanoparticles. Also 2.5 mg extract containing nanoparticles showed similar anticancer cell proliferative activity as 5 mg 5-FU. Conclusion: Our results revealed that traditional medicinal plants could be an excellent source of natural anticancer agents and the chitosan-extract nanoparticles is a promising formulation strategy to enhance their clinical effectiveness.

In recent, curiosity is at the forefront to understand the complexity of cancer driven by genetic, molecular and epigenetic programming due to life style, environmental pressure and metabolite adaptations. On the other hand, complex and heterogeneous nature of cancer is linked to the metabolic and molecular landscape of diabetic complications. This Letter to editor connects the dots and highlights the need to view cancer beyond the mirror of genetic and epigenetic aberration as metabolic disturbances. In this commentary, the author highlights the major contributions from two elegant papers from Cha et al. (2018) and Wu et al. (2018) by delineating molecular pathways that lead to the potential use of anti-diabetic drug metformin and other potential repurposing drugs towards cancer therapeutics.