Phosphatidylserine binding directly regulates TIM-3 function.

Co-signaling receptors for the T cell receptor (TCR) are important therapeutic targets, with blockade of co-inhibitory receptors such as PD-1 now central in immuno-oncology. Advancing additional therapeutic immune modulation approaches requires understanding ligand regulation of other co-signaling receptors. One poorly understood potential therapeutic target is TIM-3 (T cell immunoglobulin and mucin domain containing-3). Which of TIM-3's several proposed regulatory ligands is/are relevant for signaling is unclear, and different studies have reported TIM-3 as a co-inhibitory or co-stimulatory receptor in T cells. Here, we show that TIM-3 promotes NF-κB signaling and IL-2 secretion following TCR stimulation in Jurkat cells, and that this activity is regulated by binding to phosphatidylserine (PS). TIM-3 signaling is stimulated by PS exposed constitutively in cultured Jurkat cells, and can be blocked by mutating the PS-binding site or by occluding this site with an antibody. We also find that TIM-3 signaling alters CD28 phosphorylation. Our findings clarify the importance of PS as a functional TIM-3 ligand, and may inform the future exploitation of TIM-3 as a therapeutic target.

Drug repurposing: a systematic review on root causes, barriers and facilitators.

BACKGROUND: Repurposing is a drug development strategy receiving heightened attention after the Food and Drug Administration granted emergency use authorization of several repurposed drugs to treat Covid-19. There remain knowledge gaps on the root causes, facilitators and barriers for repurposing. METHOD: This systematic review used controlled vocabulary and free text terms to search ABI/Informa, Academic Search Premier, Business Source Complete, Cochrane Library, EconLit, Google Scholar, Ovid Embase, Ovid Medline, Pubmed, Scopus, and Web of Science Core Collection databases for the characteristics, reasons and example of companies deprioritizing development of promising drugs and barriers, facilitators and examples of successful re-purposing. RESULTS: We identified 11,814 articles, screened 5,976 for relevance, found 437 eligible for full text review, 115 of which were included in full analysis. Most articles (66%, 76/115) discussed why promising drugs are abandoned, with lack of efficacy or superiority to other therapies (n = 59), strategic business reasons (n = 35), safety problems (n = 28), research design decisions (n = 12), the complex nature of a studied disease or drug (n = 7) and regulatory bodies requiring more information (n = 2) among top reasons. Key barriers to repurposing include inadequate resources (n = 42), trial data access and transparency around abandoned compounds (n = 20) and expertise (n = 11). Additional barriers include uncertainty about the value of repurposing (n = 13), liability risks (n = 5) and intellectual property (IP) challenges (n = 26). Facilitators include the ability to form multi-partner collaborations (n = 38), access to compound databases and database screening tools (n = 32), regulatory modifications (n = 5) and tax incentives (n = 2). CONCLUSION: Promising drugs are commonly shelved due to insufficient efficacy or superiority to alternate therapies, poor market prospects, and industry consolidation. Inadequate resources and data access and challenges negotiating IP are key barriers to repurposing reaching its full potential as a core approach in drug development. Multi-partner collaborations and the availability and use of compound databases and tax incentives are key facilitators for repurposing. More research is needed on the current value of repurposing in drug development and how to better facilitate resources to support it, where valuable, especially financial, staffing for out-licensing shelved products, and legal expertise to negotiate IP agreements in multi-partner collaborations. TRIAL REGISTRATION: The protocol was registered on Open Science Framework ( https://osf.io/f634k/ ) as it was not eligible for registration on PROSPERO as the review did not focus on a health-related outcome.

Telomerase reverse transcriptase promoter alterations across cancer types as detected by next-generation sequencing: A clinical and molecular analysis of 423 patients.

BACKGROUND: Telomerase reverse transcriptase (TERT) promoter mutations that may affect telomerase activity have recently been described in human malignancies. The purpose of this study was to investigate the clinical correlates of TERT promoter abnormalities in a large cohort of patients with diverse cancers. METHODS: This study analyzed TERT promoter alterations and clinical characteristics of 423 consecutive patients for whom molecular testing by next-generation sequencing was performed between August 2014 and July 2015. RESULTS: Of the 423 patients, 61 (14.4%) had TERT promoter mutations, and this placed TERT promoter alterations among the most prevalent aberrations after tumor protein 53 (TP53; 39%) and KRAS and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) alterations (15% each) in this population. TERT promoter alterations were more frequent in men (P = .031) and were associated with brain cancers (P = .001), skin cancers/melanoma (P = .001), and a higher number of aberrations (P = .0001). A co-alteration analysis found that TERT promoter alterations were significantly correlated with CDKN2A/B (P = .001) and BRAF abnormalities (P = .0003). Patients harboring TERT promoter alterations or TP53 or CDKN2A/B alterations and those with 4 or more alterations demonstrated shorter survival (hazard ratio for normal TERT promoters vs aberrant ones, 0.44; P = .017). However, only a higher number of alterations remained significant in the multivariate analysis. CONCLUSIONS: Overall, TERT promoter alterations were among the most prevalent aberrations in this population, with very high rates in brain cancers (48% of patients) and melanomas (56% of patients). These aberrations frequently coexist with a high number of other aberrations, with the latter feature also significantly associated with poorer overall survival. Therapeutic options for targeting tumors with TERT promoter mutations are currently limited, although a variety of novel approaches are under development. Cancer 2018;124:1288-96. © 2017 American Cancer Society.

Erythrocytosis Is Rare With Exogenous Testosterone in Gender-Affirming Hormone Therapy.

CONTEXT: Studies have found a variable incidence of erythrocytosis among people using testosterone as part of gender-affirming hormone therapy (GAHT). OBJECTIVE: To examine the effect of using exogenous testosterone as GAHT on hematocrit in a large North American cohort. METHODS: We conducted a cross-sectional analysis of testosterone and hematocrit laboratory values in 6670 patients who were prescribed testosterone through Plume, a national provider of GAHT. The prevalence of erythrocytosis, the mean hematocrit at predetermined testosterone thresholds and with varying routes of testosterone administration were assessed. RESULTS: Among 6670 individuals, 560 (8.4%) had a hematocrit ≥50%, 182 ≥ 52% (2.7%), and 60 ≥ 54% (0.9%). There was significant variation (P < .001) in hematocrit between different clinically relevant testosterone thresholds (T < 50 vs T 50-299 vs T 300-999 vs T ≥ 1000 ng/dL) and when comparing serum testosterone in increments of 50 ng/dL within the target range for males (300-1000 ng/dL) (P < .001). Mean hematocrit ranged from 41.84% (T < 50 ng/dL) to 45.68% (T 900-949 ng/dL). Patients on intramuscular testosterone had a higher mean hematocrit than those on transdermal testosterone (44.96% vs 43.41%, P < .001). Both route of administration (P < .001) and testosterone level (P < .001) had statistically significant associations with hematocrit when controlling for each other. CONCLUSION: While the magnitude of change in hematocrit with serum level and route of administration of testosterone was statistically significant, the absolute levels were within the normal range, unlikely to be clinically meaningful. These findings, along with the low prevalence of erythrocytosis, should help allay concerns about the use of testosterone as GAHT.

"If we don't speak the language, we aren't offered the same opportunities": Qualitative perspectives of palliative care access for women of color living with advanced breast cancer.

Context: Despite efforts to enhance equity, disparities in early palliative care (PC) access for historically minoritized patients with advanced breast cancer (ABC) persist. Insight into patient and clinician perspectives are needed to inform future models aimed at improving equity in PC access and outcomes. Objectives: To explore qualitative barriers and facilitators to early PC access in an urban setting with Black and Latina women with ABC. Methods: In this qualitative descriptive study, we conducted one-on-one interviews with Black and Latina women with ABC (N = 20) and interdisciplinary clinicians (N = 20) between February 2022 and February 2023. Participants were recruited from urban academic and community cancer clinics. Transcripts were analyzed using an inductive coding and thematic analysis approach. Results: Barriers identified by both patients and clinicians included lack of communication between oncology, PC, and primary care teams, limited understanding of PC among patients and non-PC clinicians, language and health literacy-related communication challenges, and racism and marginalization, including implicit bias and lack of diverse racial/ethnic representation in the supportive care workforce. Facilitators identified by both patients and clinicians included patient-to-patient referrals, support groups breaking cultural stigma on topics including self-advocacy and PC, referrals from trusted providers, and community organizations' abilities to overcome challenges related to social determinants of health, most specifically logistical and financial support. Conclusions: Patients and clinicians reported similar barriers and facilitators to PC access, most commonly through the lens of care coordination and communication. These findings will inform future adaptation of a culturally and linguistically care model to improve access to early PC services for Black and Latina women with ABC.

High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with immunotherapy outcome.

Background: CTLA-4 impedes the immune system's antitumor response. There are two Food and Drug Administration-approved anti-CTLA-4 agents - ipilimumab and tremelimumab - both used together with anti-PD-1/PD-L1 agents. Objective: To assess the prognostic implications and immunologic correlates of high CTLA-4 in tumors of patients on immunotherapy and those on non-immunotherapy treatments. Design/methods: We evaluated RNA expression levels in a clinical-grade laboratory and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors, including 489 patients with advanced/metastatic cancers and full outcome annotation. A reference population (735 tumors; 35 histologies) was used to normalize and rank transcript abundance (0-100 percentile) to internal housekeeping gene profiles. Results: The most common tumor types were colorectal (140/514, 27%), pancreatic (55/514, 11%), breast (49/514, 10%), and ovarian cancers (43/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (⩾75th percentile rank). Cancers with the largest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). High CTLA-4 RNA independently/significantly correlated with high PD-1, PD- L2, and LAG3 RNA levels (and with high PD-L1 in univariate analysis). High CTLA-4 RNA expression was not correlated with survival from the time of metastatic disease [N = 272 patients who never received immune checkpoint inhibitors (ICIs)]. However, in 217 patients treated with ICIs (mostly anti-PD-1/anti-PD- L1), progression-free survival (PFS) and overall survival (OS) were significantly longer among patients with high versus non-high CTLA-4 expression [hazard ratio, 95% confidence interval: 0.6 (0.4-0.9) p = 0.008; and 0.5 (0.3-0.8) p = 0.002, respectively]; results were unchanged when 18 patients who received anti-CTLA-4 were omitted. Patients whose tumors had high CTLA-4 and high PD-L1 did best; those with high PD-L1 but non-high CTLA-4 and/or other expression patterns had poorer outcomes for PFS (p = 0.004) and OS (p = 0.009) after immunotherapy. Conclusion: High CTLA-4, especially when combined with high PD-L1 transcript expression, was a significant positive predictive biomarker for better outcomes (PFS and OS) in patients on immunotherapy.

High CTLA-4 expression and immunotherapy outcome High CTLA-4 expression was not a prognostic factor for survival in patients not receiving ICIs but was a significant positive predictive biomarker for better outcome (PFS and OS) in patients on immunotherapy, perhaps because it correlated with expression of other checkpoints such as PD-1 and PD-L2.

Outcomes and Follow-Up Data From Two Skin Cancer Screening Events.

This study investigated the outcomes and follow-up behaviors of participants from two free skin cancer screening events in the United States. This survey, with 296 participants and a 31% response rate, gathered information on participant demographics, personal history of skin cancer, knowledge of skin screening practices, and follow-up behaviors. There was a high follow-up rate of 92.3% among individuals recommended for further dermatological consultation, but a low (22%) concordance rate between the preliminary diagnoses from the screening and patient-recalled diagnoses. Additionally, about one-sixth of participants identified limited access to care as a motivation for participating in the screening. The study emphasizes the need to improve awareness about the limitations of free screenings, enhance participant education, and ensure equitable access to skin cancer screening. Future research should focus on factors influencing follow-up behaviors and the development of targeted interventions to increase awareness and access to skin cancer screening.

STK11 alterations in the pan-cancer setting: prognostic and therapeutic implications.

BACKGROUND: STK11 is an important tumour suppressor gene reported to confer immunotherapy resistance in non-small-cell lung cancers (NSCLC) especially in the presence of KRAS co-alterations. METHODS: This study analysed 4446 patients for whom next-generation sequencing of tissue and/or circulating tumour DNA (ctDNA) had been performed. RESULTS: Overall, 60 of 4446 tumours (1.35%) harboured STK11 alterations. STK11 alterations were associated with shorter median time to progression and overall survival (OS) across cancers from diagnosis: 6.4 months (5.1-7.9) versus 12 months (11.7-12.3; p = 0.001); and 20.5 (17.4-23.5) versus 29.1 (26.9-31.3; p = 0.03), respectively (pan-cancer). Pan-cancers, the median progression-free survival (PFS; 95% CI) for first-line therapy (regardless of treatment type) for those with co-altered STK11 and KRAS (N = 27; versus STK11-altered and KRAS wild type [N = 33]), was significantly shorter (3 [1.3-4.7] versus 10 [4.9-15.7] months, p < 0.0005, p multivariate, 0.06); the median OS also was also shorter (p multivariate = 0.02). In pan-cancer patients treated with checkpoint blockade, STK11 and KRAS co-altered versus STK11-altered/KRAS wild type had a shorter median PFS and trend toward shorter OS (p = 0.04 and p = 0.06, respectively). In contrast, in examining STK11-altered versus wild-type pan-cancer patients treated with checkpoint blockade immunotherapy, the two groups showed no difference in outcome (PFS [p = 0.4]; OS [p = 0.7]); STK11-altered versus wild-type lung cancer patients also did not fare worse on immunotherapy. CONCLUSIONS: Across cancers, STK11 alterations correlated with a poor prognosis regardless of therapy. However, STK11 alterations alone did not associate with inferior immunotherapy outcome in the pan-cancer setting or in NSCLC. Pan-cancer patients with co-altered STK11/KRAS did worse, regardless of treatment type.

Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors.

The Wnt/beta-catenin pathway is a family of proteins that is implicated in many vital cellular functions such as stem cell regeneration and organogenesis. Several intra-cellular signal transduction pathways are induced by Wnt, notably the Wnt/beta-catenin dependent pathway or canonical pathway and the non-canonical or beta-catenin-independent pathway; the latter includes the Wnt/Ca2+ and Planar Cell Polarity pathway (PCP). Wnt activation occurs at the intestinal crypt floor, and is critical to optimal maintenance of stem cells. Colorectal cancers show evidence of Wnt signaling pathway activation and this is associated with loss of function of the tumor regulator APC. Wnt activation has been observed in breast, lung, and hematopoietic malignancies and contributes to tumor recurrence. The Wnt pathway cross talks with the Notch and Sonic Hedgehog pathways, which has implications for therapeutic interventions in cancers. There are significant challenges in targeting the Wnt pathway, including finding agents that are efficacious without damaging the system of normal somatic stem cell function in cellular repair and tissue homeostasis. Here, we comprehensively review the Wnt pathway and its interactions with the Notch and Sonic Hedgehog pathways. We present the state of the field in effectors and inhibitors of Wnt signaling, including updates on clinical trials in various cancers with inhibitors of Wnt, Notch, and Sonic Hedgehog.

Liquid Biopsies for Cancer: Coming to a Patient near You.

The use of circulating tumor DNA (ctDNA) as a novel and non-invasive test for the diagnosis and surveillance of cancer is a rapidly growing area of interest, with sequencing of ctDNA acting as a potential surrogate for tissue biopsy. Circulating tumor DNA has been detected incidentally during noninvasive prenatal testing and additionally in more than 75% of known cancer patients participating in ctDNA studies evaluating its sensitivity. In the setting of mutation-based targeted tumor therapy, it shows a concordance rate >80% when compared with gold-standard tissue biopsies. Through ctDNA detection and sequencing, a simple blood test becomes a liquid biopsy for cancer, surveying a patient's entire circulation with the goal of early detection, prognostic information, personalized therapy options, and tracking for recurrence or resistance, all with fewer or no tissue biopsies. Given the recent first-ever FDA approval of a liquid biopsy, it is important for clinicians to be aware of the rapid advancements likely to bring these tests into our practices soon. Here we review the biology, clinical implications, and recent advances in circulating tumor DNA analysis.

Utility of Genomic Analysis In Circulating Tumor DNA from Patients with Carcinoma of Unknown Primary.

Carcinoma of unknown primary (CUP) is a rare and difficult-to-treat malignancy, the management of which might be improved by the identification of actionable driver mutations. We interrogated 54 to 70 genes in 442 patients with CUP using targeted clinical-grade, next-generation sequencing of circulating tumor DNA (ctDNA). Overall, 80% of patients exhibited ctDNA alterations; 66% (290/442) ≥1 characterized alteration(s), excluding variants of unknown significance. TP53-associated genes were most commonly altered [37.8% (167/442)], followed by genes involved in the MAPK pathway [31.2% (138/442)], PI3K signaling [18.1% (80/442)], and the cell-cycle machinery [10.4% (46/442)]. Among 290 patients harboring characterized alterations, distinct genomic profiles were observed in 87.9% (255/290) of CUP cases, with 99.7% (289/290) exhibiting potentially targetable alterations. An illustrative patient with dynamic changes in ctDNA content during therapy and a responder given a checkpoint inhibitor-based regimen because of a mismatch repair gene anomaly are presented. Our results demonstrate that ctDNA evaluation is feasible in CUP and that most patients harbor a unique somatic profile with pharmacologically actionable alterations, justifying the inclusion of noninvasive liquid biopsies in next-generation clinical trials. Cancer Res; 77(16); 4238-46. ©2017 AACR.