The identification and validation of a targeted therapy for patients with triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. One of the key reasons for the failure to develop a new therapy for this subgroup of breast cancer patients has been the difficulty in identifying a highly prevalent, targetable molecular alteration in these tumors. Recently however, the p53 gene was found to be mutated in approximately 80% of basal/TNBC, raising the possibility that targeting the mutant p53 protein product might be a new approach for the treatment of this form of breast cancer. In this study, we investigated the anti-cancer activity of PRIMA-1 and PRIMA-1 MET (APR-246), two compounds which were previously reported to reactivate mutant p53 and convert it to a form with wild-type (WT) properties. Using a panel of 18 breast cancer cell lines and 2 immortalized breast cell lines, inhibition of proliferation by PRIMA-1 and PRIMA-1 MET was found to be cell-line dependent, but independent of cell line molecular subtype. Although response was independent of molecular subtype, p53 mutated cell lines were significantly more sensitive to PRIMA-1 MET than p53 WT cells (p 5 0.029). Furthermore, response (measured as IC 50 value) correlated significantly with p53 protein level as measured by ELISA (p 5 0.0089, r520.57, n 5 19). In addition to inhibiting cell proliferation, PRIMA-1 MET induced apoptosis and inhibited migration in a p53 mutant-dependent manner. Based on our data, we conclude that targeting mutant p53 with PRIMA-1 MET is a potential new approach for treating p53-mutated breast cancer, including the subgroup with triple-negative (TN) disease.
Protein Phosphatase 2A (PP2A) is a major serine/threonine phosphatase in cells. It consists of a catalytic subunit (C), a structural subunit (A), and a regulatory/variable B-type subunit. PP2A has a critical role to play in homeostasis where its predominant function is as a phosphatase that regulates the major cell signaling pathways in cells. Changes in the assembly, activity and substrate specificity of the PP2A holoenzyme have a direct role in disease and are a major contributor to the maintenance of the transformed phenotype in cancer. We have learned a lot about how PP2A functions from specific mutations that disrupt the core assembly of PP2A and from viral proteins that target PP2A and inhibit its effect as a phosphatase. This prompted various studies revealing that restoration of PP2A activity benefits some cancer patients. However, our understanding of the mechanism of action of this is limited because of the complex nature of PP2A holoenzyme assembly and because it acts through a wide variety of signaling pathways. Information on PP2A is also conflicting as there are situations whereby inactivation of PP2A induces apoptosis in many cancer cells. In this review we discuss this relationship and we also address many of the pertinent and topical questions that relate to novel therapeutic strategies aimed at altering PP2A activity.
Cancer health disparities remain stubbornly entrenched in the US health care system. The Affordable Care Act was legislation to target these disparities in health outcomes. Expanded access to health care, reduction in tobacco use, uptake of other preventive measures and cancer screening, and improved cancer therapies greatly reduced cancer mortality among women and men and underserved communities in this country. Yet, disparities in cancer outcomes remain. Underserved populations continue to experience an excessive cancer burden. This burden is largely explained by health care disparities, lifestyle factors, cultural barriers, and disparate exposures to carcinogens and pathogens, as exemplified by the COVID-19 epidemic. However, research also shows that comorbidities, social stress, ancestral and immunobiological factors, and the microbiome, may contribute to health disparities in cancer risk and survival. Recent studies revealed that comorbid conditions can induce an adverse tumor biology, leading to a more aggressive disease and decreased patient survival. In this review, we will discuss unanswered questions and new opportunities in cancer health disparity research related to comorbid chronic diseases, stress signaling, the immune response, and the microbiome, and what contribution these factors may have as causes of cancer health disparities.
Signalling proteins are intrinsic to all biological processes and interact with each other in tightly regulated and orchestrated signalling complexes and pathways. Characterization of protein binding can help to elucidate protein function within signalling pathways. This information is vital for researchers to gain a more comprehensive knowledge of cellular networks which can then be used to develop new therapeutic strategies for disease. However, studying protein-protein interactions (PPIs) can be challenging as the interactions can be extremely transient downstream of specific environmental cues. There are many powerful techniques currently available to identify and confirm PPIs. Choosing the most appropriate range of techniques merits serious consideration. The aim of this review is to provide a starting point for researchers embarking on a PPI study. We provide an overview and point of reference for some of the many methods available to identify interactions from in silico analysis and large scale screening tools through to the methods used to validate potential PPIs. We discuss the advantages and disadvantages of each method and we also provide a workflow chart to highlight the main experimental questions to consider when planning cell lysis to maximize experimental success.
ImportanceNeighborhood variables may be factors in the excessive burden of prostate cancer among African American men.ObjectiveTo examine associations between neighborhood deprivation, circulating immune-oncology markers, and prostate cancer among African American and European American men.Design, Setting, and ParticipantsA case-control study was conducted between January 1, 2005, and January 1, 2016. Participants included men with prostate cancer and age- and race-frequency-matched population controls. Participants were recruited at the Baltimore Veterans Affairs Medical Center and University of Maryland Medical Center; controls were obtained through the Maryland Motor Vehicle Administration database. National Death Index follow-up was performed through December 31, 2020, and data analysis was conducted from February 1, 2022, through October 31, 2022.Exposures2000 Census-tract Neighborhood Deprivation Index as a standardized score.Main Outcomes and MeasuresPrimary outcomes included prostate cancer, all-cause mortality, and disease-specific mortality. Secondary outcomes included the National Comprehensive Cancer Network risk score and serum proteomes for 82 immune-oncology markers with pathway annotation.ResultsParticipants included men with prostate cancer (n = 769: 405 African American, 364 European American men) and age- and race-frequency-matched population controls (n = 1023: 479 African American, 544 European American men). The median survival follow-up was 9.70 years (IQR, 5.77 years), with 219 deaths. Among 884 African American men, mean (SD) age at recruitment was 63.8 (7.6) years; mean (SD) age at recruitment among 908 European American men was 66.4 (8.1) years. In the multivariable logistic regression analysis with individual socioeconomic status adjustment, neighborhood deprivation was associated with 55% increased odds of prostate cancer among African American men (odds ratio [OR], 1.55; 95% CI, 1.33-1.81), but was not associated with the disease among European American men. Residing in the most-deprived vs least-deprived neighborhoods corresponded to 88% higher disease odds (OR, 1.88; 95% CI, 1.30-2.75) among all men and an approximate 3-fold increase among African American men (OR, 3.58; 95% CI, 1.72-7.45), but no association was noted among European American men. In Cox proportional hazard regression analyses, socioeconomic status–adjusted neighborhood deprivation was associated with an increased all-cause mortality only among African American men (hazard ratio [HR], 1.28; 95% CI, 1.08-1.53), whereas it was associated with metastatic disease and a 50% increased hazard of a prostate cancer–specific death among all men (HR, 1.50; 95% CI, 1.07-2.09). In analyses restricted to controls, neighborhood deprivation was associated with increased activity scores of serum proteome-defined chemotaxis, inflammation, and tumor immunity suppression.Conclusions and RelevanceThe findings of this study suggest that deprived neighborhood residency may increase the risk of African American men for prostate cancer and a related mortality, potentially through its association with systemic immune function and inflammation.
In the present paper we have developed, described and validated an in vitro bioassay to monitor skeletal muscle proliferation and differentiation. We have also demonstrated the use of this assay to evaluate factors which may affect muscle protein balance.
Conventional therapies for cancer such as chemotherapy and radiotherapy remain a mainstay in treatment, but in many cases a targeted approach is lacking, and patients can be vulnerable to drug resistance. In recent years, novel concepts have been emerging to improve the traditional therapeutic options in cancers with poor survival outcomes. New therapeutic strategies involving areas like energy metabolism and extracellular vesicles along with advances in immunotherapy and nanotechnology are driving the next generation of cancer treatments. The development of fields such as theranostics in nanomedicine is also opening new doors for targeted drug delivery and nano-imaging. Here we discuss the use of innovative technologies presented at the Irish Association for Cancer Research (IACR) Annual Meeting, highlighting examples of where new approaches may lead to promising new treatment options for a range of cancer types.
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