tbuckley/cabot-search huggingface dataset:
Cell Type–specific Adaptive Signaling Responses to KRASG12C Inhibition
Authors: Hitendra S. Solanki, Eric A. Welsh, Bin Fang, Victoria Izumi, Lancia Darville, Brandon Stone, Ryan Franzese, Sandip Chavan, Fumi Kinose, Denis Imbody, John M. Koomen, Uwe Rix, Eric B. Haura
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Covalent inhibitors of KRASG12C specifically target tumors driven by this form of mutant KRAS, yet early studies show that bypass signaling drives adaptive resistance. Although several combination strategies have been shown to improve efficacy of KRASG12C inhibitors (KRASi), underlying mechanisms and predictive strategies for patient enrichment are less clear. Experimental Design: We performed mass spectrometry–based phosphoproteomics analysis in KRASG12C cell lines after short-term treatment with ARS-1620. To understand signaling diversity and cell type–specific markers, we compared proteome and phosphoproteomes of KRASG12C cells. Gene expression patterns of KRASG12C cell lines and lung tumor tissues were examined. Results: Our analysis suggests cell type–specific perturbation to ERBB2/3 signaling compensates for repressed ERK and AKT signaling following ARS-1620 treatment in epithelial cell type, and this subtype was also more responsive to coinhibition of SHP2 and SOS1. Conversely, both high basal and feedback activation of FGFR or AXL signaling were identified in mesenchymal cells. Inhibition of FGFR signaling suppressed feedback activation of ERK and mTOR, while AXL inhibition suppressed PI3K pathway. In both cell lines and human lung cancer tissues with KRASG12C, we observed high basal ERBB2/3 associated with epithelial gene signatures, while higher basal FGFR1 and AXL were observed in cells/tumors with mesenchymal gene signatures. Conclusions: Our phosphoproteomic study identified cell type–adaptive responses to KRASi. Markers and targets associated with ERBB2/3 signaling in epithelial subtype and with FGFR1/AXL signaling in mesenchymal subtype should be considered in patient enrichment schemes with KRASi.
Abstract PS17-16: Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models
Authors: Maysoun Shomali, Fangxian Sun, Mikhail Levit, Jack Pollard, Joon Sang Lee, Laurent Schio, Youssef El-Ahmad, Chris Soria, Patrick Cohen, Laurent Debussche, Monsif Bouaboula
Journal: Cancer Research (2021)

Abstract Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERDs), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models including MCF7-ESR1 wild type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those have resistance to endocrine therapy with both wild-type and mutant ER. This presentation will highlight the global profile and key features of new SERD and its translation to patient. Citation Format: Maysoun Shomali, Fangxian Sun, Mikhail Levit, Jack Pollard, Joon Sang Lee, Laurent Schio, Youssef El-Ahmad, Chris Soria, Patrick Cohen, Laurent Debussche, Monsif Bouaboula. Sar439859, a novel selective estrogen receptor degrader (serd), demonstrates effective and broad antitumor activity in wild-type and mutant er-positive breast cancer models [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS17-16.
Sirtuin 2 Prevents Liver Steatosis and Metabolic Disorders by Deacetylation of Hepatocyte Nuclear Factor 4α
Authors: Huihui Ren, Fuqing Hu, Dan Wang, Xiaonan Kang, Xiaohui Feng, Lu Zhang, Bowen Zhou, Siyue Liu, Gang Yuan
Journal: Hepatology (2021)

Background and Aims Sirtuin 2 (SIRT2), an NAD + ‐dependent deacetylase, is involved in various cellular processes regulating metabolic homeostasis and inflammatory responses; however, its role in hepatic steatosis and related metabolic disorders is unknown. Approach and Results Integrating the published genomic data on NAFLD samples from humans and rodents available in the Gene Expression Omnibus, we found that SIRT2 was significantly down‐regulated in livers from patients with advanced NAFLD and high‐fat diet (HFD)–induced NAFLD mice. This study further revealed that SIRT2 was markedly decreased in obese (ob/ob) mice and in palmitate‐treated HepG2 cells. Restoration of hepatic SIRT2 expression in ob/ob or HFD‐fed mice largely alleviated insulin resistance, hepatic steatosis, and systematic inflammation, whereas SIRT2 liver‐specific ablation exacerbated these metabolic dysfunctions in HFD‐fed C57BL/6J mice. Mechanistically, SIRT2 stabilized the hepatocyte nuclear factor 4α (HNF4α) protein by binding to and deacetylating HNF4α on lysine 458. Furthermore, HNF4α was sufficient to mediate SIRT2 function, and SIRT2‐HNF4α interaction was required for SIRT2 function both in vivo and in vitro . Conclusions Collectively, the present study provided evidence that SIRT2 functions as a crucial negative regulator in NAFLD and related metabolic disorders and that targeting the SIRT2‐HNF4α pathway may be a promising strategy for NAFLD treatment.
Abstract PS14-17: Rapamycin inhibits stem cell function and diminishes inflammation and senescence markers in human mammary gland
Authors: Hakim Bouamar, Larry Broome, Xiang Gu, Alia Nazarullah, Andrew Brenner, Virginia Kaklamani, Ismail Jatoi, Lu-Zhe Sun
Journal: Cancer Research (2021)

Abstract Gene expression profiles of some subtypes of breast cancer were shown to correspond to the profiles of the basal or luminal mammary stem/progenitor cell-enriched epithelial cells implicating the mammary stem cells (MaSCs) as tumor-initiating cells for certain types of breast cancer. Moreover, there is growing evidence that MaSCs may initiate neoplastic transformation when dysregulated in mouse models. We have previously reported an increased frequency of the MaSC-enriched Lin-/CD49fhigh/CD24+ basal cells in old mice (&amp;gt;27 month) compared to young ones (2-4 month) along with an increase of hyperplasic lesions. Gene expression profile revealed an increase of immune and inflammatory responses in old basal cells and stroma cells indicating that aging-induced immune and inflammatory responses might initiate basal cell expansion and transformation. Our preliminary data on mice using rapamycin, an immune and inflammation inhibitor, were very encouraging so we decided to start a clinical window trial (NCT02642094) to test whether rapamycin could reduce biomarkers associated with progression to invasive breast cancer and MaSC numbers in postmenopausal patients with atypical ductal hyperplasia (ADH) or ductal carcinoma in situ (DCIS). The patients enrolled in the trial took rapamycin (sirolimus, 2mg/day) for 5-7 days with 3-7 days of washout before surgery. The adjacent non-tumor surgical tissues were used for the measurements of sphere formation efficiency (SFE) of the basal and luminal cells. The control group were patients with ADH/DCIS who did not take the drug. Rapamycin treatment significantly diminished the SFE of the basal MaSC. Immunohistochemical staining of the biopsies and surgical tissues showed that rapamycin treatment significantly decreased the levels of COX2 (an inflammation marker) and p16 (a senescence marker), and moderately increased p62 (an autophagy marker). Furthermore, rapamycin significantly reduced the proliferation marker Ki67 staining. In conclusion, rapamycin inhibits MaSCs function and senescence and inflammation features in human mammary glands. Whether the suppression of the senescence-associated inflammatory responses is the mechanism by which rapamycin suppresses MaSC function is under investigation. Citation Format: Hakim Bouamar, Larry Broome, Xiang Gu, Alia Nazarullah, Andrew Brenner, Virginia Kaklamani, Ismail Jatoi, Lu-Zhe Sun. Rapamycin inhibits stem cell function and diminishes inflammation and senescence markers in human mammary gland [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS14-17.
Use of <scp>sodium–glucose</scp> co‐transporter 2 inhibitors in patients with heart failure and type 2 diabetes mellitus: data from the Swedish Heart Failure Registry
Authors: Peter M. Becher, Benedikt Schrage, Giulia Ferrannini, Lina Benson, Javed Butler, Juan Jesus Carrero, Francesco Cosentino, Ulf Dahlström, Linda Mellbin, Giuseppe M.C. Rosano, Gianfranco Sinagra, Davide Stolfo, Lars H. Lund, Gianluigi Savarese
Journal: European Journal of Heart Failure (2021)

Use of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in real-world heart failure (HF) is poorly characterised. In contemporary patients with HF and type 2 diabetes mellitus (T2DM) we assessed over time SGLT2i use, clinical characteristics and outcomes associated with SGLT2i use.Type 2 diabetes patients enrolled in the Swedish HF Registry between 2016-2018 were considered. We performed multivariable logistic regression models to assess the independent predictors of SGLT2i use and Cox regression models in a 1:3 propensity score-matched cohort and relevant subgroups to investigate the association between SGLT2i use and outcomes. Of 6805 eligible HF patients with T2DM, 376 (5.5%) received SGLT2i, whose use increased over time with 12% of patients on treatment at the end of 2018. Independent predictors of SGLT2i use were younger age, HF specialty care, ischaemic heart disease, preserved kidney function, and absence of anaemia. Over a median follow-up of 256 days, SGLT2i use was associated with a 30% lower risk of cardiovascular (CV) death/first HF hospitalisation (hazard ratio 0.70, 95% confidence interval 0.52-0.95), which was consistent regardless of ejection fraction, background metformin treatment and kidney function. SGLT2i use was also associated with a lower risk of all-cause and CV death, HF and CV hospitalisation, and CV death/myocardial infarction/stroke.In a contemporary HF cohort with T2DM, SGLT2i use increased over time, was more common with specialist care, younger age, ischaemic heart disease, and preserved renal function, and was associated with lower mortality and morbidity.
Mechanical Load Regulates Excitation-Ca <sup>2+</sup> Signaling-Contraction in Cardiomyocyte
Authors: Rafael Shimkunas, Bence Hegyi, Zhong Jian, John A. Shaw, Mohammad A. Kazemi-Lari, Debika Mitra, J. Kent Leach, Xiaocen Li, Mark Jaradeh, Nicholas Balardi, Yi-Je Chen, Ariel L. Escobar, Anthony J. Baker, Julie Bossuyt, Tamas Banyasz, Nipavan Chiamvimonvat, Kit S. Lam, Donald M. Bers, Leighton T. Izu, Ye Chen-Izu
Journal: Circulation Research (2021)
Priorities of Unmet Needs for Those Affected by Colorectal Cancer: Considerations From a Series of Nominal Group Technique Sessions
Authors: Sharyn F. Worrall, Andrea J. Dwyer, Reese M. Garcia, Keavy E. McAbee, Anjelica Q. Davis
Journal: Journal of the National Comprehensive Cancer Network (2021)

Background: Colorectal cancer (CRC) is the third most common cancer among men and women in the United States. Patients and survivors experience a range of challenges, including anxiety, financial issues, long-term adverse effects, and more. The intent of this project was to assess the needs of the CRC community directly from survivors and their caregivers and to lay a foundation for ongoing support. Methods : Twelve nominal group technique sessions were facilitated. Participants were randomized and presented with the following questions: “What information do you wish you had at the time of diagnosis?” and “What information do you need now as a survivor?” After the nominal group technique process, each statement’s score was divided by the number of people in the session, providing the average to identify the top-ranked statements. Themes and subthemes were applied to statements. Results were compared between coders. Results: There was a total of 79 participants, 49 of whom self-identified as a patient with or survivor of cancer. Patient/survivor demographics were as follows: stage IV disease (n=20), stage III disease (n=22), stage II disease (n=5), stage I disease (n=2), caregiver/family member (n=30), male (n=16), female (n=63), White (n=50), Native Hawaiian/Pacific Islander (n=1), Hispanic/Latino (n=13), Black/African American (n=11), Asian (n=1), and more than one race/ethnicity (n=3). The most frequent themes among responses to the first question were communication and coordination with care team and access to CRC resources. The most frequent themes among responses to the second question were psychosocial support and family/caregiver support. Frequent themes among responses across both questions were understanding treatment options and adverse effects. Conclusions: These findings highlight gaps in support for individuals affected by CRC, and lay a foundation for ongoing assistance. Future studies exploring differences based on disease stage, race/ethnicity, age, gender identity, geographic location, and tumor location are needed to further tailor support for those experiencing CRC. Themes identified in this project require a multidisciplinary approach to ensure that the unmet needs of survivors are addressed.
Impact of C-reactive protein flare-response on oncological outcomes in patients with metastatic renal cell carcinoma treated with nivolumab
Authors: Shohei Fukuda, Kazutaka Saito, Yosuke Yasuda, Toshiki Kijima, Soichiro Yoshida, Minato Yokoyama, Junichiro Ishioka, Yoh Matsuoka, Yukio Kageyama, Yasuhisa Fujii
Journal: Journal for ImmunoTherapy of Cancer (2021)

Background The dynamic change in C-reactive protein (CRP) levels, CRP kinetics, is a prognostic factor for metastatic renal cell carcinoma (mRCC) in the tyrosine kinase inhibitor era. We investigated the impact of early CRP kinetics on the efficacy of nivolumab in patients with mRCC. Methods We performed a retrospective analysis of 42 mRCC patients who were treated with nivolumab as a second-line or later therapy between 2016 and 2019. All patients had received previous TKI therapy. Patients were divided into three groups based on their early CRP kinetics: CRP levels increased to more than double compared with baseline within 1 month after initiation of nivolumab (flare) and then decreased to a lower value than baseline within 3 months (CRP flare-responders); CRP levels decreased by ≥30% within 3 months without “flare” (CRP responders); and the remaining patients (non-CRP responders). The maximum tumor shrinkage, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated. The association of the early CRP kinetics and oncological outcomes was assessed. Results The median follow-up period was 8 months. The median baseline CRP level was 23 mg/L. CRP flare-responders, CRP responders, and non-CRP responders included 11 (26%), 15 (36%), and 16 (38%) patients, respectively. Thirteen patients (31%) died of mRCC. The maximum changes in target lesions from baseline of CRP flare-responder, CRP-responder, and non-CRP responder groups were −38%, −13%, and 16%, on average, respectively (p&lt;0.001). ORRs of these three groups were 73%, 27%, and 6%, respectively (p&lt;0.001). The median PFS values of each group were not reached, 12 months, and 2.4 months (p=0.005), and the median OS values were not reached, not reached, and 12 months (p=0.048). In a multivariate analysis, early CRP kinetics was a significant independent factor for objective response, PFS, and OS (p&lt;0.001, p=0.004, and p=0.006, respectively). Conclusions CRP flare-response was associated with significant tumor shrinkage and improved survival outcomes in patients with mRCC who were treated with nivolumab. Early CRP kinetics could be useful for evaluating nivolumab treatment efficacy.
Abstract PS6-59: Impact of Cholecystectomy in Breast Cancer Recurrence
Authors: Isheeta Madeka, Rohin Gawdi, Katherine L Cook, Akiko Chiba
Journal: Cancer Research (2021)

Abstract Background: Several published studies demonstrate that bile acid metabolites may influence the growth of breast cancer cells in vitro. Our group has shown reduced plasma concentrations of cholic acid and chenodeoxycholic acid (primary bile acids) and deoxycholic acid and lithocholic acid (secondary bile acids) in breast cancer patients that later on develop tumor recurrence. Cholecystectomy reduces the circulating bile acid pool. In patients with prior cholecystectomy, changes in bile acid metabolites may contribute to breast cancer tumorigenesis and recurrence. This study investigates our institutional rate of cholecystectomy in women diagnosed with breast cancer and its impact on breast cancer recurrence. Methods: A retrospective review of patients with an invasive breast cancer diagnosis between 2014-2015 was conducted. Demographics, preoperative variables, surgical history and clinical outcome data was collected. 5-year disease-free survival (DFS) was compared using a Log-rank (Mantel-Cox) test. Results: The study included 264 patients with mean age of 60.9. Most were Caucasian (83.5%). The majority were diagnosed at Stage II or lower (80.3%) and had hormone receptor positive, HER2 negative breast cancer (72.9%). Approximately 22.7% of patients had prior cholecystectomy surgery. The only statistically significant heterogeneity in demographic data between patients with and without cholecystectomy was body mass index (BMI). Patients with cholecystectomy had a mean BMI of 33.3, versus 29.1 in patients with intact gallbladders. The 5-year DFS in breast cancer patients with cholecystectomy was 91.6%, versus 97.1% in patients with intact gallbladders (p=0.06). Conclusion: Women with breast cancer who had a history of cholecystectomy had increased rates of breast cancer recurrence over a 5-year period compared to women with breast cancer with intact gallbladders. Although this result was not statistically significant, a trend was seen. Future study of a larger patient sample size sample may lead to a statistical significant difference. The statistically significant difference in BMI between the two patient groups is likely a confounding factor, given increased BMI is a known risk factor for developing cholecystitis and breast cancer. This data supports existing in vitro studies that bile acids may influence the growth of breast cancer cells. There may be utility in closer follow-up of women with breast cancer and a history of cholecystectomy given the increased rate of breast cancer recurrence in this population. Citation Format: Isheeta Madeka, Rohin Gawdi, Katherine L Cook, Akiko Chiba. Impact of Cholecystectomy in Breast Cancer Recurrence [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-59.
Abstract PS18-48: Comprehensive analysis of solute carriers to characterise differential expression in breast cancer cell lines and human tissue
Authors: Rachel Jane Sutherland, Annette Meeson, Simon Lowes
Journal: Cancer Research (2021)

Abstract Essential nutrient uptake required for cell growth and survival is mediated by Solute Carrier (SLC) transporters both physiologically and in cancers. The SLC super-family encompasses sub-families of transport proteins including organic anion transporters (OAT), organic cation transporters (OCT) and organic anion transporting polypeptides (OATP). SLCs transport a vast array of endogenous and exogenous substances, including estrogen, its conjugates, and clinically relevant anti-cancer drugs. Accumulating evidence suggests that SLC transporters are differentially expressed in hormone-responsive and hormone non-responsive breast cancers, which could influence breast cancer pathogenesis, both in disease progression and treatment resistance. We investigated whether SLC transporters are differentially expressed in different breast cancer cell lines and in human breast cancer tissue. First, bulk cells from the breast cancer cell lines MCF-7 (hormone responsive) and MDA-MB-231 (hormone non-responsive) were analysed for differential expression of SLCs using sq-PCR and RT-PCR. 8 of 11 SLCO and 10 of 14 SLC22 transporters were expressed in at least one cell line. Transporter expression was either similar or lower in MCF-7 cells compared to MDA-MB-231 cells, with the exception of SLCO2A1, SLCO4C1, SLCO5A1 and SLC22A5 which were higher in MCF-7 cells. mRNA expression of SLCs was then compared between both cell lines and human breast cancer tissue. The latter showed an expression pattern largely reminiscent of the MCF-7 cells. Because these techniques measure the average level of expression shown by a pooled cell population, there is the potential disadvantage that cell heterogeneity is masked. To help address this, Single Cell RNA Sequencing (scRNA-Seq) was performed using the 10x Genomics Chromium Single Cell 3’ platform and NovaSeq Technologies to compare SLC transporter expression between the cell lines. Together these results provide evidence for differences in SLC transporter expression between cell lines and cancer tissues that may contribute to cancer progression. Citation Format: Rachel Jane Sutherland, Annette Meeson, Simon Lowes. Comprehensive analysis of solute carriers to characterise differential expression in breast cancer cell lines and human tissue [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-48.
Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial
Authors: Jeff P Sharman, Danielle M Brander, Anthony R Mato, Nilanjan Ghosh, Stephen J Schuster, Suman Kambhampati, John M Burke, Frederick Lansigan, Marshall T Schreeder, Scott D Lunin, Alexander Zweibach, Mikhail Shtivelband, Patrick M Travis, Jason C Chandler, Kathryn S Kolibaba, Peter Sportelli, Hari P Miskin, Michael S Weiss, Ian W Flinn
Journal: The Lancet Haematology (2021)
Four keys to unlock IgG
Authors: Falk Nimmerjahn, Jeffrey V. Ravetch
Journal: The Journal of Experimental Medicine (2021)

The identification of discrete subclasses within the immunoglobulin G (IgG) isotype by Grey and Kunkel (1964. J. Exp. Med.https://doi.org/10.1084/jem.120.2.253) provided the framework for our current understanding of differential IgG subclass activity in protective and self-reactive immune responses.