Critical Reviews in Oncogenesis最新文献

Nitric oxide (NO) and the enzyme that synthesizes it, nitric oxide synthase 2 (NOS2), have emerged as key players in inflammation and cancer. Expression of NOS2 in tumors has been correlated both with positive outcomes and with poor prognoses. The chemistry of NO is the major determinate to the biological outcome and the concentration of NO, which can range over five orders of magnitude, is critical in determining which pathways are activated. It is the activation of specific oncogenic and immunological mechanisms that shape the outcome. The kinetics of specific reactions determine the mechanisms of action. In this review, the relevant reactions of NO and related species are discussed with respect to these oncogenic and immunological signals.

The pioneering studies of Dr. Larry Keefer and colleagues with diazeniumdiolates or NONOates as a platform have unraveled the chemical biology of many nitric oxides and have led to the design of a variety of promising therapeutic agents in oncology, gastroenterology, antimicrobials, wound healing, and the like. This dedication to Dr. Larry Keefer briefly highlights some of his studies using the diazeniumdiolate platform in the cancer arena.

The application of radiotherapy to the treatment of cancer has existed for over 100 years. Although its use has cured many, much work remains to be done to minimize side effects, and in-field tumor recurrences. Resistance of the tumor to a radiation-mediated death remains a complex issue that results in local recurrence and significantly decreases patient survival. Here, we review mechanisms of radioresistance and selective treatment combinations that improve the efficacy of the radiation that is delivered. Further investigation into the underlying mechanisms of radiation resistance is warranted to develop not just novel treatments, but treatments with improved safety profiles relative to current radiosensitizers. This review is written in memory and honor of Dr. Peter Stambrook, an avid scientist and thought leader in the field of DNA damage and carcinogenesis, and a mentor and advocate for countless students and faculty.

Oral cancer has become a significant problem throughout the world, particularly in countries that are still developing. Recent literature supports the contribution of components of the tumor microenvironment (TME) and the effect of epigenetic changes happening in the cells of the TME on oral cancer development and progression. In this review, we comprehensively examine the significance of TME in the development of OC along with the current understanding of the epigenetic modifications that regulate the TME and their cohesive impact on tumor traits and their potential as therapeutic targets.

Prostate cancer (PCa) is one of the leading causes of cancer diagnoses and cancer-related deaths in the United States. Mutations or deletions in the genes involved in the DNA damage response (DDR) are common in aggressive primary PCa (germline alterations) and further enriched in advanced therapy-resistant PCa (somatic alterations). Among the DDR genes, BRCA2 is the most commonly altered (~ 13%) in advanced therapy-resistant PCa. Patients with BRCA2-altered PCas are exquisitely sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis). Indeed, two PARPis-olaparib and rucaparib have recently gained U.S. Food & Drug Administration approval for the treatment of advanced PCas harboring a BRCA2 mutation. This review seeks to explore the role of BRCA2 in DNA damage repair, the pathogenesis and progression of BRCA2 mutant PCa, and the utility of radiation therapy, targeted therapies, and platinum-based chemotherapies for patients with BRCA2 alterations.

Treatment options for men with metastatic prostate cancer have greatly expanded in the last decade. Androgen receptor pathway inhibitors, taxane cytotoxic therapy, poly(ADP-ribose) polymerase inhibitors, and radionuclide theranostics against prostate-specific membrane antigen have collectively contributed to incremental improvements in both quality and longevity of life for patients with metastatic castration-resistant prostate cancer (mCRPC). Despite these successes, few studies inform on optimal therapy selection and sequencing across this crowded treatment landscape. Genomic analysis of both tissue and liquid biopsy specimens shows promise in bridging this practice gap, with alterations in several key prostate cancer driver genes demonstrating clear associations with clinical outcomes, as well as informing use of novel precision medicine targeted therapies. In this review, we evaluate the current evidence of genomic alterations in various oncogenic signaling pathways as clinical biomarkers in mCRPC, focusing on correlative studies that analyzed outcomes based on findings in plasma cell-free DNA. We highlight the pitfalls of interpreting genomic findings in samples with substandard tumor content, and suggest pathologic and disease factors to consider when embarking upon tumor genotyping to guide treatment decisions in metastatic prostate cancer. As access to life-prolonging therapies improves, and barriers to cost-effective genotyping and reliable data interpretation are overcome, we anticipate that predictive and prognostic biomarkers that inform on disease biology, drug sensitivity, and therapy resistance will inevitably be integrated into the routine care of patients with metastatic prostate cancer.

Prostate cancer is the second most common malignancy in men worldwide, and incidence is likely to rise in the next decade. The current screening options have limitations and have been shown to result in over-treatment of clinically insignificant disease. New biomarkers and technologies to detect them are therefore needed to better diagnose and stratify patients in primary care. Circulating cell-free DNA (ccfDNA) has gained interest as a potential minimally invasive biomarker, detectable in many bodily fluids (such as blood, urine, and cerebral spinal fluid) and reflecting the mutational landscape in tumors. More recently, the size distribution of ccfDNA fragments has also gained interest as a specific biomarker, where differences in size distribution have been observed between healthy volunteers and cancer patients, resulting in the new field of fragmentomics. Analysis of ccfDNA sizes provides avenues for alternative analytical technologies but commercial options are currently limited. Most focus on mutation detection and are subject to several biases that may affect size distribution. Here, we discuss the available technologies and identify major issues and considerations that may affect their implementation as a clinically useful test based on ccfDNA size profiling.