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Background PD-1 inhibitors have shown significant efficacy in triple negative breast cancer (BC), however, durable responses are less common in estrogen receptor-positive (ER+) BC. Better markers are therefore needed that will identify likely responders to PD-1 inhibitors among patients with luminal BC. While most efforts have focused on the immune checkpoint protein PD-L1, the alternative PD-1 ligand, PD-L2, has been largely overlooked. We aimed to determine if PD-L2 is associated with unfavorable prognosis in ER+ BC. Methods PD-L2 protein levels in cancer cells and stromal cells were measured retrospectively by quantitative immunofluorescence histocytometry in tissue microarrays of therapy-naïve, localized or locoregional ER+ BC and correlated with progression-free survival (PFS). Evaluable tumor PD-L2 data were derived from a main study cohort A diagnosed between 1988-2005 (n=684) with extensive clinical and outcome data and from an independent validation cohort B diagnosed between 1992-2012 (n=273). Patients received standard-of-care adjuvant therapy without immune checkpoint inhibitors after tumor resection. Results Univariate analysis of the main cohort A revealed that high PD-L2 expression in cancer cells was associated with shorter PFS (HR=1.8; 95%CI:1.3-2.6; p=0.001), an observation that was validated in an independent cohort B (HR=2.3, 95%CI:1.1-4.8; p=0.026). Approximately one third of ER+ BC cases were classified as high PD-L2. After multivariable adjustment for common clinicopathological variables, high cancer cell levels of PD-L2 remained independently predictive of early recurrence (HR=2.0; 95%CI:1.4-2.9; p< 0.001). Sub-analysis of ER+ BC cases treated with adjuvant chemotherapy (n=197) suggested that high PD-L2 levels in cancer cells was associated with particularly increased risk of progression (multivariable HR=3.4; 95%CI:1.9-6.2; p< 0.001). The observed frequent expression of PD-L2 protein in BC provided scientific rationale for the design of our ongoing phase II clinical trial (NCT04243616) of neoadjuvant combined PD-1 inhibitor (cemiplimab; Regeneron Pharmaceuticals Inc) and chemotherapy in patients diagnosed with PD-L1+ and/or PD-L2+ BC. The primary objective of this trial is to assess pathologic responses to neoadjuvant treatment with secondary objective of assessing the correlation between PD-L1/PD-L2 status and tumor responses. Pathologist review of PD-L1 and PD-L2 expression in an initial set of ER+ tumors (n=15) screened for trial eligibility revealed frequent discordance between cancer cell positivity for PD-L1 and PD-L2 protein (PD-L1: median=0%; range 0-2% vs. PD-L2: median=18%; range < 1-60%) as well as immune cell positivity (PD-L1: median=5%; range 0-50% vs. PD-L2: median=0; range 0-50%). Conclusions In treatment-naïve ER+ breast tumors, high cancer cell expression of PD-L2 protein was an independent predictor of poor clinical outcome, with evidence of further elevated risk of progression in patients who received adjuvant chemotherapy. Preliminary analyses of ER+ tumors from our ongoing clinical trial showed frequent discordance between baseline PD-L1 and PD-L2 protein expression in both cancer cells and immune cells. Collectively, our analyses indicate that PD-L2 has prognostic value for ER+ BC, and our progress justify further studies to determine whether PD-L2, alone or in combination with PD-L1, may serve as a predictive marker of response to PD-1 inhibitors. Citation Format: Lubna N. Chaudhary, Inna Chervoneva, Amy R. Peck, Yunguang Sun, Misung Yi, John F. Langenheim, Julie M. Jorns, Sailaja Kamaraju, Yee Chung Cheng, John Burfeind, Christopher R. Chitambar, Jeffrey A. Hooke, Albert J. Kovatich, Craig Shriver, Hai Hu, Juan P. Palazzo, Marluce Bibbo, Terry Hyslop, Richard Pestell, Edith P. Mitchell, Hallgeir Rui. High PD-L2 Protein Expression in Cancer Cells is an Independent Marker of Unfavorable Prognosis in Luminal Breast Tumors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-13.

Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR+), and human epidermal growth factor receptor two negative (HER2−) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials.

Recent therapeutic successes have renewed interest in drug combinations, but experimental screening approaches are costly and often identify only small numbers of synergistic combinations. The DREAM consortium launched an open challenge to foster the development of in silico methods to computationally rank 91 compound pairs, from the most synergistic to the most antagonistic, based on gene-expression profiles of human B cells treated with individual compounds at multiple time points and concentrations. Using scoring metrics based on experimental dose-response curves, we assessed 32 methods (31 community-generated approaches and SynGen), four of which performed significantly better than random guessing. We highlight similarities between the methods. Although the accuracy of predictions was not optimal, we find that computational prediction of compound-pair activity is possible, and that community challenges can be useful to advance the field of in silico compound-synergy prediction., Multiscale Analysis of Genomic and Cellular Networks (MAGNet 5U54CA121852-08); Library of Integrated Network-based Cellular Signatures Program (LINCS 1U01CA164184-02--3U01HL111566-02); National Institutes of Health (NIH 5R01CA152301); Cancer Prevention and Research Institute of Texas (CPRIT RP101251); NIH, NCI (U54 CA112970)

Diet and obesity, and their associated metabolic alterations, are some of the fastest-growing causes of disease and death in America. Findings from epidemiological studies correlating obesity, the sources of dietary fat and prostate cancer (PCa) are conflicting. We have previously shown that 15% of PB-ErbB-2 x pten(+/-) mice developed PCa and exhibited increased phosphorylated 4E-BP1, but not the key PI3-kinase intermediary phospho-protein, mTOR, when maintained on unrefined mouse chow. We report herein that 100% of animals fed refined, westernized AIN-93-based diets containing corn oil developed PCa by 12 months of age. Increases in visceral fat and mTO R activation in the tumors were also observed. Furthermore, nuclear cyclin E levels were significantly induced by the AIN-93-corn oil-based diets versus chow. Replacing 50% of the corn oil with menhaden oil, with 21% of its triglycerides being n-3 PUFA's, had no effect on tumorigenesis, fat deposition, cyclin E or mTOR. Phosphorylated BAD levels were similar in the tumors of mice in all three diets. Our data demonstrated that in the context of our preclinical model, components of crude chow, but not dietary n-3 PUFAs, protect against PCa progression. In addition, these data establish phosphorylated mTOR, nuclear cyclin E and visceral fat deposits as possible biomarkers of increased dietary risk for PCa.

This study assessed the effects of gender, faculty, and year (level) on “authoritarianism” among university students within the faculties of law and medicine. A questionnaire, using the Ray Adapted F Scale to measure authoritarianism, was administered to 454 students at the University of Western Australia. The first, third and sixth year medical students were compared with first, third and final year law students. Gender alone was responsible for a significant source of variance, with males more authoritarian than females. Faculty alone showed a strong trend towards significance with medicine more authoritarian than law. Although no other 2– or 3– way interactions were significant a trend was apparent in which females became more and males less authoritarian with increasing level.

Tbx3 encodes a transcriptional repressor that is important for diverse patterning events during development, and Tbx3 mutation in humans causes the ulnar-mammary syndrome. Here, we describe the identification of Tbx3 in array-based search for genes downstream Wnt/β-catenin that are implicated in liver tumorigenesis. Overexpression of Tbx3 is closely associated with the mutational status of β-catenin in murine liver tumors induced by Myc as well as in human hepatocellular carcinomas and hepatoblastomas. Moreover, Tbx3 transcription is activated by ectopic expression of β-catenin in mouse liver and in human tumor cell lines. Evidence that Tbx3 transcription is directly regulated by β-catenin is provided by chromatin immunoprecipitation and reporter assays. Although HepG2 cells stably transfected with Tbx3 display moderately enhanced growth rate, the dominant negative mutant Tbx3-Y149S drastically inhibits hepatoma cell growth in vitro and in vivo. Moreover, small interfering RNAs (siRNA) directed against Tbx3 inhibit anchorage-independent growth of liver and colon carcinoma cells. We further show that inhibition of Tbx3 expression by specific siRNAs blocks β-catenin–mediated cell survival and renders cells sensitive to doxorubicin-induced apoptosis. Conversely, ectopic expression of Tbx3 inhibits apoptosis induced by β-catenin depletion. Marked overexpression of Tbx3 in a subset of hepatoblastomas is associated with chemotherapy-resistant phenotype and unfavorable patient outcome. These results reveal an unsuspected role of Tbx3 as a mediator of β-catenin activities on cell proliferation and survival and as an important player in liver tumorigenesis. [Cancer Res 2007;67(3):901–10]