Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer.

Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) approach, we find that agonist-liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinct transcriptional outcomes in prostate cancer cells. Further analysis on clinical prostate tissues reveals that the binding of AR to these two distinct motifs is involved in prostate carcinogenesis. Together, these results suggest that unique ligands may switch DNA motifs recognized by ligand-dependent transcription factors in vivo. Our findings also provide a broad mechanistic foundation for understanding ligand-specific induction of gene expression profiles.

An overview of the unique challenges facing African-American breast cancer survivors.

PURPOSE: The existence of cancer disparities is well known. Focus on alleviating such disparities centers on diagnosis, treatment, and mortality. This review surveyed current knowledge of health disparities that exist in the acute survivorship period (immediately following diagnosis and treatment) and their contributors, particularly for African-American breast cancer survivors (AA-BCS). METHODS: Utilizing the ASCO four components of survivorship care, we explore disparities in surveillance and effects of cancer and therapies that AA-BCS face within the acute survivorship period (the years immediately following diagnosis). A literature review of PUBMED, Scopus, and Cochrane databases was conducted to identify articles related to AA-BCS acute survivorship. The search yielded 97 articles. Of the 97 articles, 38 articles met inclusion criteria. RESULTS: AA-BCS experience disparate survivorship care, which negatively impacts quality of life and health outcomes. Challenges exist in surveillance, interventions for late effects (e.g., quality-of-life outcomes, cardiotoxicity, and cognitive changes), preventing recurrence with promotion of healthy living, and coordinating care among the healthcare team. CONCLUSIONS: This overview identified current knowledge on the challenges in survivorship among AA-BCS. Barriers to optimal survivorship care inhibit progress in eliminating breast cancer disparities. Research addressing best practices for survivorship care is needed for this population. Implementation of culturally tailored care may reduce breast cancer disparities among AA-BCS.

Three-tiered role of the pioneer factor GATA2 in promoting androgen-dependent gene expression in prostate cancer.

In prostate cancer, androgen receptor (AR) binding and androgen-responsive gene expression are defined by hormone-independent binding patterns of the pioneer factors FoxA1 and GATA2. Insufficient evidence of the mechanisms by which GATA2 contributes to this process precludes complete understanding of a key determinant of tissue-specific AR activity. Our observations suggest that GATA2 facilitates androgen-responsive gene expression by three distinct modes of action. By occupying novel binding sites within the AR gene locus, GATA2 positively regulates AR expression before and after androgen stimulation. Additionally, GATA2 engages AR target gene enhancers prior to hormone stimulation, producing an active and accessible chromatin environment via recruitment of the histone acetyltransferase p300. Finally, GATA2 functions in establishing and/or sustaining basal locus looping by recruiting the Mediator subunit MED1 in the absence of androgen. These mechanisms may contribute to the generally positive role of GATA2 in defining AR genome-wide binding patterns that determine androgen-responsive gene expression profiles. We also find that GATA2 and FoxA1 exhibit both independent and codependent co-occupancy of AR target gene enhancers. Identifying these determinants of AR transcriptional activity may provide a foundation for the development of future prostate cancer therapeutics that target pioneer factor function.

Safety and efficacy of peptide receptor radionuclide therapy in neuroendocrine tumors: A single center experience.

Peptide receptor radionucleotide therapy (PRRT) with 177Lu-dotatate is widely used for the treatment of patients with neuroendocrine tumors (NETs). We analyzed data from 104 patients with NETs treated with 177Lu -dotatate at a US academic center between December 2017 and October 2020 to better understand patterns of long-term efficacy, safety, and toxicity in the real-world setting. 177Lu-dotatate (200 mCi) was administered every eight weeks for four doses. The most common sites of primary disease were small intestine NETs (n = 49, 47%), pancreatic NETs (n = 32, 31%), and lung NETs (n = 7, 7%). Twenty-seven percent had Ki-67 <3%, 49% had Ki-67 between 3-20%, and 13.5% had Ki-67 >20%. The cohort had been pretreated with a median of two prior lines of treatment. Forty percent had received prior liver-directed treatment. Seventy-four percent of patients completed all four doses of treatment. The objective response rate was 18%. The median time-to-treatment failure/death was significantly longer for small-bowel NETs when compared to pancreatic NETs (37.3 months vs. 13.2 months, p = 0.001). In a multivariate model, Ki-67, primary site, and liver tumor burden ≥50% were found to independently predict time-to-treatment failure/death. Around 40% of patients experienced adverse events of ≥grade 3 severity. Treatment-related adverse events leading to discontinuation of therapy happened in 10% of patients. Preexisting mesenteric/peritoneal disease was present in 33 patients; seven of these patients developed bowel-related toxicities including two grade 5 events. We also report two cases of delayed-onset minimal change nephrotic syndrome, which occurred 14 and 27 months after the last dose of PRRT. Lastly, we describe six patients who developed rapid tumor progression in the liver leading to terminal liver failure within 7.3 months from the start of PRRT, and identify potential risk factors associated with this occurrence, which will need further study.

Assessment of Food Safety Knowledge and Behaviors of Cancer Patients Receiving Treatment.

Cancer patients receiving treatment are at a higher risk for the acquisition of foodborne illness than the general population. Despite this, few studies have assessed the food safety behaviors, attitudes, risk perceptions, and food acquisition behaviors of this population. Further, no studies have, yet, quantified the food safety knowledge of these patients. This study aims to fill these gaps in the literature by administering a thorough questionnaire to cancer patients seeking treatment in three hospitals in a Midwest, metropolitan area. Demographic, treatment, food security, and food safety knowledge, behaviors, attitudes, risk perceptions, and acquisition information was assessed for 288 patients. Specific unsafe attitudes, behaviors, and acquisition practices were identified. Most notable is that 49.4% (n = 139) of participants were not aware that they were at increased risk of foodborne infection, due to their disease and treatment. Additionally, though patients exhibited a general understanding of food safety, the participant average for correctly answering the food safety questions was 74.77% ± 12.24%. The section concerning food storage showed lowest participant knowledge, with an average score of 69.53% ± 17.47%. Finally, patients reporting low food security also reported a higher incidence of unsafe food acquisition practices (P < 0.05). These findings will help healthcare providers to better educate patients in the food safety practices necessary to decrease risk of foodborne infection, and to provide targeted food safety education to low-food-security patients.

Remarkable response to a novel ATR inhibitor in a patient with poorly differentiated neuroendocrine carcinoma.

M6620 (formerly known as VX-970) is a potent inhibitor of ataxia telangiectasia and Rad3-related protein (ATR), a serine/threonine-specific protein kinase involved in activation of checkpoint signaling and promotion of cell cycle arrest in response to DNA damage (inhibition constant [Ki] <300 pM, IC50 of 20 nM). ATR inhibition enhances the cytotoxic effect of DNA damaging drugs and infrared radiation (IR) in many cancer cell lines and primary human tumors. M6620 is currently under investigation in early-phase clinical trials for the treatment of a number of malignancies. Below, we report a case of a patient with metastatic prostate cancer with clonal evolution to poorly differentiated large cell neuroendocrine carcinoma who developed an exceptional response to treatment with M6620 and cisplatin on a phase I trial VX12-970-001 (NCT02157792: An Open-Label, First-in-Human Study of the Safety, Tolerability, and Pharmacokinetics of VX-970 in Combination With Cytotoxic Chemotherapy) with over 20 months of non-CNS progression free survival. We will discuss the mechanism of action of M6620, rationale for enrolling the patient in this trial and hypothesize the reasons for this exceptional response.

An Evaluation of Factors Predicting Diet Quality among Cancer Patients.

A high diet quality is associated with a lower risk of cancer mortality. However, the predictive factors of diet quality among cancer patients are not well understood. This study determines the socio-demographic and disease-related factors that affect diet quality among cancer patients. Two hundred and forty-two cancer patients completed questionnaires assessing sociodemographic and disease-related characteristics. Diet quality was measured using the Healthy Eating Index 2010 (HEI). Independent sample t-tests and one-way ANOVA with post-hoc analysis using the Tukey HSD test were used to compare mean HEI scores across these characteristics. A regression model was used to determine factors that predicted diet quality. The overall HEI score among cancer patients was 61.59 (SD = 11.67). Patients with a high school degree or General Education Diploma (GED) or less had lower HEI scores (ß = -4.03, p = 0.04; ß = -7.77, p = 0.001, respectively) compared to those with college degrees. Additionally, homemakers had significantly higher HEI scores (ß = 7.95, p = 0.008) compared to those who worked at least 40 hours per week. Also, individuals with some types of cancers (e.g., endometrial or uterine) had significantly higher HEI scores (ß = 12.56, p = 0.002) than those with other cancers (e.g., head and neck). Our findings will help oncology healthcare providers identify and target cancer patients with specific demographic characteristics who are at increased risk for consuming poor-quality diets with much needed food resource interventions.

IGF-1 and IGFBP-3 gene variants influence on serum levels and prostate cancer risk in African-Americans.

Insulin-like growth factor (IGF)-1 and Insulin-like growth factor binding protein-3 (IGFBP-3) are strong inhibitors of apoptosis and play a role in mediating the effects of growth hormone. Both IGF-1 and IGFBP-3 serum levels have been linked to cancer risk. Here, we explore the relationship between three common IGF polymorphisms [C/T single-nucleotide polymorphism (SNP) (rs7965399) and a dinucleotide repeat (CA)n within the 5' regulatory region of the IGF-1 gene and the -202 A/C SNP in the IGFBP-3 gene], serum levels and prostate cancer (Pca) risk in 767 African-Americans enrolled in a clinic-based case-control study. IGF-1 and IGFBP-3 levels were measured using immunochemiluminometric assay and the three polymorphisms were typed for 401 Pca cases and 366 age- and ethnicity-matched controls. Multiple linear regression and multivariable unconditional logistic regression were used to test for associations between genotypes and circulating IGF levels and Pca risk, respectively. The presence of at least one copy of the IGFBP-3 -202 C allele was strongly associated with lower IGFBP-3 serum levels (3532 versus 3106 ng/ml; P = 0.008). We also observed a 2-fold increase in Pca risk for individuals homozygous for the IGFBP-3 -202 C allele [odds ratio = 2.4; 95% confidence interval = 1.2-4.8). Furthermore, IGF-1 (CA)19 genotypes were significantly associated with lower IGFBP-3 serum levels (P = 0.003). Our results reveal that variation in the 5'-untranslated region of the IGF-1 and IGFBP-3 genes may be influencing IGF serum levels and Pca risk in African-Americans and suggest a need to explore this variation across diverse populations. Our study adds clarity and further support to the previous findings, implicating serum IGFBP-3 levels and the IGFBP-3 -202 A/C SNP in prostate carcinogenesis.