Repurposing antipsychotics of the diphenylbutylpiperidine class for cancer therapy.

The recent development of high throughput compound screening has allowed drug repurposing to emerge as an effective avenue for discovering novel treatments for cancer. FDA-approved antipsychotic drugs fluspirilene, penfluridol, and pimozide are clinically used for the treatment of psychotic disorders, primarily schizophrenia. These compounds, belong to diphenylbutylpiperidine class of antipsychotic drugs, are the potent inhibitors of dopamine D2 receptor and calcium channel. A correlation has been found that patients treated for schizophrenia have lower incidences of certain types of cancer, such as respiratory, prostate, and bladder cancers. These compounds have also been shown to inhibit cancer proliferation in a variety of cancer cells, including melanoma, lung carcinoma, breast cancer, pancreatic cancer, glioma, and prostate cancer, among others. Antipsychotic drugs induce apoptosis and suppress metastasis in in vitro and in vivo models through mechanisms involving p53, STAT3, STAT5, protein phosphatase 2A, cholesterol homeostasis, integrins, autophagy, USP1, wnt/ß-catenin signaling, and DNA repair. Additionally, pre-clinical evidence suggests that penfluridol and pimozide act synergistically with existing chemotherapeutic agents, such as dasatinib, temozolomide, and cisplatin. Some studies have also reported that the cytotoxic activity of the antipsychotics is selective for dividing cells. Based on this growing body of evidence and the availability and previous FDA-approval of the drugs, the compounds appear to be promising anti-cancer agents.

Sex-Based Differences in Melanoma Survival Improvement from 2004 to 2018.

Background: Melanoma is the deadliest form of skin cancer and its incidence and mortality vary by sex, age, race, and socioeconomic status. Relatively few studies, however, have characterized disparities in survival improvement across these demographic groups in melanoma. METHODS: Survival data from the Surveillance, Epidemiology, and End Results (SEER) database were obtained from 2004 to 2018. The compiled data were analyzed for cancer-specific survival (CSS) to produce multivariable Cox regressions that estimate sex-based survival disparities across patient demographic groups. Additionally, time-to-progression and survival analyses were conducted for a cohort of patients with carcinoma-in situ (CIS) that developed into melanoma. RESULTS: In both female and male patients, melanoma diagnosis in more recent years (2014-2018 versus 2004-2008) was associated with an improved CSS, with females demonstrating an HR of 0.55 (95% CI: 0.49-0.60) and males demonstrating an HR of 0.49 (0.46-0.53). The trend remained consistent upon analyzing the effects of both sex and race on survival improvement for White and Hispanic males and females, but the results were not significant for Black and Asian patients. Joint sex and age analysis demonstrated significant reductions in HR across all age groups for female and male patients with a diagnosis in more recent years. Analysis of lesions progressing from CIS to melanoma (high-risk CIS) demonstrated an increased OR for males over females (OR: 1.70; 95% CI: 1.55-1.85), while survival analysis demonstrated no difference between sexes in the HR. Finally, for male patients, high-risk CIS demonstrated worse CSS compared to female patients with high-risk CIS (OR: 1.43; 95% CI: 1.15-1.79). CONCLUSION: Overall, melanoma survival has improved in recent years, though some patient subgroups have experienced a lower improvement in survival from 2004 to 2018.

Predicting Chemotherapy Benefit across Different Races in Early-Stage Breast Cancer Patients Using the Oncotype DX Score.

BACKGROUND: Oncotype DX assay, a multigene molecular test, has been widely used to stratify relapse risk and guide chemotherapy treatment in breast cancer. However, the optimal threshold of the Oncotype DX score in predicting chemotherapy benefit and its racial variation has not been investigated. METHODS: In this study, we apply a random forest survival model to the SEER-Oncotype cohort data (Surveillance, Epidemiology, and End Results with Oncotype DX test information for breast cancer patients) and determine chemotherapy benefit thresholds in early-stage, estrogen-receptor-positive (ER+), and HER2-negative (HER2-) patients of different races. RESULTS: Our results indicate that early-stage ER+, HER2-, and LN-/LN+ patients may benefit from receiving chemotherapy at a lower Oncotype DX score than current guidelines (Recurrence Score, RS > 25 or RS > 30) suggest. According to the estimated chemotherapy sensitivity thresholds from our models, 2.05-2.72-fold more lymph-node-negative (LN-) and 2.08-5.02-fold more lymph-node-positive (LN+) patients who may not currently be recommended for chemotherapy by their Oncotype DX test result may actually have the potential to benefit from chemotherapy. Furthermore, our models indicate a racial difference in chemotherapy benefit: white, black, and Asian women with early-stage ER+/LN- tumors benefit from chemotherapy when their Oncotype DX scores are greater than 19.9, 37.2, and 18.0, respectively. CONCLUSIONS: Our study provides a method for calibrating multigene molecular tests to help guide treatment decisions in racially and ethnically diverse patients with cancer. Specifically, we identify key chemotherapy sensitivity thresholds for the Oncotype DX recurrence score test in breast cancer patients and provide evidence that certain patients may benefit from receiving chemotherapy at a lower threshold than the current clinical guidelines suggest.

Cutaneous Dermal Metastasis of Inflammatory Breast Carcinoma Mimicking Granuloma Annulare.

Breast cancer can present as a wide range of cutaneous lesions at the time of diagnosis or months to years after a known diagnosis of breast cancer. Cutaneous sequela of breast cancer, including metastasis, have a diverse range of clinical appearances. Here, we describe the case of a 59-year-old female with stage IV metastatic inflammatory breast carcinoma presenting with a chronic worsening rash on her anterior chest wall. Biopsy results demonstrated metastatic carcinoma cells within the dermal lymphatics, consistent with primary breast cancer. To our knowledge, based on a thorough review of the literature, no previous case reports detailing cutaneous metastasis of breast cancer have identified a rash mimicking granuloma annulare. The present case highlights the importance of early dermatologic referral if any abnormal or persistent lesions appear in a patient with a history of or current treatment for breast cancer.

A comprehensive analysis of lung cancer highlighting epidemiological factors and psychiatric comorbidities from the All of Us Research Program.

Lung cancer is the leading cause of cancer-related mortality in the United States. Investigating epidemiological and clinical parameters can contribute to an improved understanding of disease development and management. In this cross-sectional, case-control study, we used the All of Us database to compare healthcare access, family history, smoking-related behaviors, and psychiatric comorbidities in light smoking controls, matched smoking controls, and primary and secondary lung cancer patients. We found a decreased odds of primary lung cancer patients versus matched smoking controls reporting inability to afford follow-up or specialist care. Additionally, we found a significantly increased odds of secondary lung cancer patients having comorbid anxiety and insomnia when compared to matched smoking controls. Our study provides a profile of the psychiatric disease burden in lung cancer patients and reports key epidemiological factors in patients with primary and secondary lung cancer. By using two controls, we were able to separate smoking behavior from lung cancer and identify factors that were mediated by heavy smoking alone or by both smoking and lung cancer.

An Atlas Characterizing the Shared Genetic Architecture of Inflammatory Bowel Disease with Clinical and Behavioral Traits.

BACKGROUND: Inflammatory bowel disease (IBD) development is a complex, multifactorial process that involves extrinsic and intrinsic factors such as host genetics, the immune system, the gut microbiome, and environmental risks. To help understand the genetic contribution of clinical, behavioral, psychiatric, and diet-related traits, we aim to provide a deep and comprehensive characterization of the shared genetic architecture between IBD and hundreds of potentially related traits. METHODS: Utilizing publicly available summary statistics from a previously published IBD genome-wide association study and hundreds of traits from the United Kingdom BioBank (UKBB), we performed linkage disequilibrium score regression (LDSR) analysis to estimate cross-trait genetic correlations between Crohn's disease (CD), ulcerative colitis (UC), and IBD summary statistics with the UKBB traits of interest. RESULTS: Nominally significant (P < .05) genetic correlations were observed for 181 traits in overall IBD, 239 traits in CD, and 94 traits in UC. We replicate the known association between smoking behavior and CD/UC, namely that current tobacco smoking has a positive genetic correlation with CD (rg = 0.12, P = 4.2 × 10-4), while "ever smoking" has a negative genetic correlation with UC (rg = -0.07, P = .042). Globally, all 3 strata (IBD, CD, and UC) demonstrated increased genetic correlations for psychiatric-related traits related to anxiety and depression. CONCLUSION: The present analysis reveals the shared genetic architecture between multiple traits and IBD, CD, and UC. Understanding the relevance of joint occurrences of IBD with psychiatric diseases may moderate management of these diseases for individuals jointly affected by them.

This study provides an atlas of the genetic correlation between hundreds of United Kingdom Biobank (UKBB) traits with inflammatory bowel disease (IBD), Crohn's disease (CD), and ulcerative colitis (UC). Notable strong correlations are seen between IBD and various psychiatric traits.

Multitrait genome-wide analyses identify new susceptibility loci and candidate drugs to primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare autoimmune bile duct disease that is strongly associated with immune-mediated disorders. In this study, we implemented multitrait joint analyses to genome-wide association summary statistics of PSC and numerous clinical and epidemiological traits to estimate the genetic contribution of each trait and genetic correlations between traits and to identify new lead PSC risk-associated loci. We identified seven new loci that have not been previously reported and one new independent lead variant in the previously reported locus. Functional annotation and fine-mapping nominated several potential susceptibility genes such as MANBA and IRF5. Network-based in silico drug efficacy screening provided candidate agents for further study of pharmacological effect in PSC.