tbuckley/cabot-search huggingface dataset:
Abstract 5327: KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both <i>in vitro</i> and <i>in vivo</i>
Authors: Chuansheng Ge, Lei Zhang, Baisong Liao
Journal: Cancer Research (2020)

Abstract Prostate cancer is the common cancer in men and the second leading cause of cancer-related deaths in men. This disease depends on dihydrotestosterone (DHT) which activates the androgen receptor (AR) signal. Endocrine therapy (including castration surgery, anti-androgen deprivation therapy or combined androgen blockade therapy) is a preferred treatment for prostate cancer. The treatment is very effective for the majority of patients at the initial stage, but after a median period of treatment for 14 to 30 months, most patients will gradually develop metastatic castration resistant prostate cancer (mCRPC) with a median survival of less than 20 months, and urgently need a further treatment. Androgen receptor antagonists in combination with anti-androgen drugs are currently the most effective drug treatment to manage mCRPC where castration has failed. Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide belong to this class of androgen receptor or androgen synthesis inhibitors. Here we show that KPG-121, a small molecule immunomodulator, significantly enhances the therapeutic effects of Enzalutamide, Abiraterone Acetate, Apalutamide and Darolutamide in pre-clinical mCRPC tumor models. The phase 1 trials were initiated to evaluate the safety, PK profile and preliminary efficacy of the combinatorial therapy in the patients with metastatic castration resistant prostate cancer in the US (IND 134979). KPG-121 is a novel generation of Lenalidomide analogue. KPG-121 is structurally similar to lenalidomide but with stronger binding with CRBN target, enhanced immunomodulatory activity, better anti-proliferative and anti-angiogenic properties compared to lenalidomide. Results from in vivo metastatic castration resistant prostate cancer xenograft models demonstrated that KPG-121 at tested daily dose levels ranging from 1.0 mg/kg to 10 mg/kg in combination with Enzalutamide, Abiraterone Acetate, Apalutamide or Darolutamide significantly improved anti-tumor efficacy compared to the AR signaling inhibitors alone. In addition, KPG-121 showed favorable DMPK profiles and potentially manageable toxicity in pre-clinical IND enabling study. Citation Format: Chuansheng Ge, Lei Zhang, Baisong Liao. KPG-121, a novel CRBN modulator, potently inhibits growth of metastatic castration resistant prostate cancer as a single agent or in combination with androgen receptor signaling inhibitors both in vitro and in vivo [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5327.
Abstract 3685: Sustained Ret expression during mammary gland post-lactation induces premature involution and enhances cancer potential
Authors: Sabrina A. Vallone, Martín García Solá, Robert D. Cardiff, Roberto P. Meiss, Lewis A. Chodosh, Carolina Shere-Levy, Edith C C. Kordon, Nancy E. Hynes, Albana Gattelli
Journal: Cancer Research (2020)

Abstract Loss of normal development is a hallmark of cancer. Thus, understanding the mechanisms of tissue-specific developmental regulation and the changes that occur during tumorigenesis may provide insights of both diagnostic and therapeutic importance. In breast cancer, several members of the receptor tyrosine kinases (RTK) family that are well known to promote aggressive breast cancers also have roles in normal breast. We found that Ret, a RTK member, is normally expressed in the mouse glands in lactation. We determined that inhibition of Ret activity in vivo does not alter lactation, however impacts in the transition to involution. Involution is the period with high inflammation which returns the lactating mammary gland to a quiescent state after weaning. Involution has been well described as a post-lactation stage that drives cancer progression. Ret is overexpressed in about 40% of human breast tumors. Previously, using a doxycycline-inducible transgenic mouse model (Ret/MTB) we determined that chronic expression of Ret is oncogenic in the mammary epithelium. However, the stage of development at which Ret expression results in increase mammary tumor incidence has not been identified. To address this, we used the Ret/MTB system, to conditionally overexpress Ret during discrete periods of mammary gland development. We found that Ret is required for efficient transition to involution. We determined that the induction of Ret in Ret/MTB females promotes the expression of factors that drives involution, including premature Stat3 activation. RNA-seq data in Ret-overexpressing glands is supporting these findings, which were confirmed by several techniques. In addition, sustained expression of Ret during post-lactation enhances cancer potential showing a significant increase in pre-neoplastic lesions, defective milk recycling and disrupting Stat3 signaling. These results demonstrate that Ret deregulation increases cancer potential in post-lactation and might be considered as a prognostic marker for post-partum breast cancer. Citation Format: Sabrina A. Vallone, Martín García Solá, Robert D. Cardiff, Roberto P. Meiss, Lewis A. Chodosh, Carolina Shere-Levy, Edith C C. Kordon, Nancy E. Hynes, Albana Gattelli. Sustained Ret expression during mammary gland post-lactation induces premature involution and enhances cancer potential [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3685.
Abstract 4877: Discovery of paralog-specific SUMO1 and SUMO2 functions using human cancer knockout cells
Authors: Danielle Bouchard, Wei-Chih Yang, Michael J. Matunis
Journal: Cancer Research (2020)

Abstract Small ubiquitin-related modifiers (SUMOs) are ∼100-amino acid polypeptides that function as posttranslational protein modifications and thereby regulate many essential cellular processes, many of which are relevant to cancer. Vertebrates express five SUMO paralogs (SUMO1-5), of which, SUMO1 and SUMO2 are the most widely studied. Biochemical and in vivo studies suggest that SUMO1 and SUMO2 have non-redundant functions, however, the full range of their distinct activities are not fully understood. Understanding these unqiue functions and their molecular bases could lead to more precise therapeutic interventions that target the SUMO pathway. To help define SUMO paralog-specific functions, we used CRISPR-Cas9 to knockout (KO) individual SUMO genes in osteosarcoma U2OS cells. We observed that SUMO2 KO cells were unique in exhibiting a change in cell morphology, changing from epithelial-like to fibroblast-like, thus revealing a potential role for SUMO2 in affecting cell shape. To test the hypothesis that the observed change in morphology is driven in part by changes in gene expression, we sequenced the transcriptome of the parental and SUMO KO cell lines. In alignment with the observed change in SUMO2 KO cell shape, differentially expressed genes (DEGs) involved in the extracellular matrix, basement membrane and epithelial to mesenchymal transition were uniquely enriched in SUMO2 KO cells. Further consistent with SUMO1 and SUMO2 having unique effects on transcription, we found a significantly greater number of unique DEGs in SUMO2 KO cells as compared to SUMO1 KO cells. Furthermore, an overwhelming number of DEGs were down-regulated in the SUMO1 KO cells, suggesting a specific role for SUMO1 in activating, or maintaining, gene expression. In contrast, DEGs in SUMO2 KOs were equally up and down regulated. Collectively, our findings demonstrate that SUMO1 and SUMO2 have unique biological roles and we look forward to better characterizing these paralog-specific functions in future studies. Citation Format: Danielle Bouchard, Wei-Chih Yang, Michael J. Matunis. Discovery of paralog-specific SUMO1 and SUMO2 functions using human cancer knockout cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4877.
Program Directors Survey on Diversity in Cardiovascular Training Programs
Authors: Julie B. Damp, Michael W. Cullen, Victor Soukoulis, Marty C. Tam, Friederike K. Keating, Sakima A. Smith, Deepak Bhakta, Islam Abudayyeh, Atif Qasim, Audrey Sernyak, Alex Auseon, Paul Theriot, Gaby Weissman
Journal: Journal of the American College of Cardiology (2020)
Dynamic regulation of hypoxia-inducible factor-1α activity is essential for normal B cell development
Authors: Natalie Burrows, Rachael J. M. Bashford-Rogers, Vijesh J. Bhute, Ana Peñalver, John R. Ferdinand, Benjamin J. Stewart, Joscelin E. G. Smith, Mukta Deobagkar-Lele, Girolamo Giudice, Thomas M. Connor, Akimichi Inaba, Laura Bergamaschi, Sam Smith, Maxine G. B. Tran, Evangelia Petsalaki, Paul A. Lyons, Marion Espeli, Brian J. P. Huntly, Kenneth G. C. Smith, Richard J. Cornall, Menna R. Clatworthy, Patrick H. Maxwell
Journal: Nature Immunology (2020)
Biodegradable and Electroactive Regenerated Bacterial Cellulose/MXene (Ti<sub>3</sub>C<sub>2</sub>T<i><sub>x</sub></i>) Composite Hydrogel as Wound Dressing for Accelerating Skin Wound Healing under Electrical Stimulation
Authors: Lin Mao, Sanming Hu, Yihua Gao, Li Wang, Weiwei Zhao, Lina Fu, Haoyan Cheng, Lin Xia, Shangxian Xie, Weiliang Ye, Zhijun Shi, Guang Yang
Journal: Advanced Healthcare Materials (2020)

Traditional wound dressings mainly participate in the passive healing processes and are rarely engaged in active wound healing by stimulating skin cell behaviors. Electrical stimulation (ES) has been known to regulate skin cell behaviors. Herein, a series of multifunctional hydrogels based on regenerated bacterial cellulose (rBC) and MXene (Ti3 C2 Tx ) are first developed that can electrically modulate cell behaviors for active skin wound healing under external ES. The composite hydrogel with 2 wt% MXene (rBC/MXene-2%) exhibits the highest electrical conductivity and the best biocompatibility. Meanwhile, the rBC/MXene-2% hydrogel presents desired mechanical properties, favorable flexibility, good biodegradability, and high water-uptake capacity. An in vivo study using a rat full-thickness defect model reveals that this rBC/MXene hydrogel exhibits a better therapeutic effect than the commercial Tegaderm film. More importantly, in vitro and in vivo data demonstrate that coupling with ES, the hydrogel can significantly enhance the proliferation activity of NIH3T3 cells and accelerate the wound healing process, as compared to non-ES controls. This study suggests that the biodegradable and electroactive rBC/MXene hydrogel is an appealing candidate as a wound dressing for skin wound healing, while also providing an effective synergistic therapeutic strategy for accelerating wound repair process through coupling ES with the hydrogel dressing.
Exploring the stage-specific roles of Tcf-1 in T cell development and malignancy at single-cell resolution
Authors: Fang Wang, Zhihong Qi, Yingpeng Yao, Guotao Yu, Tao Feng, Tianyan Zhao, Hai-Hui Xue, Yaofeng Zhao, Peng Jiang, Li Bao, Shuyang Yu
Journal: Cellular and Molecular Immunology (2020)
Abstract 3748: Tyrosine kinase inhibition of fibroblast growth factor receptor 1 in advanced prostate cancer
Authors: Louise Medina Bengtsson, Estefania Labanca, Nora Navone
Journal: Cancer Research (2020)

Abstract Advanced prostate cancer (PCa) is one of the leading causes of cancer death in men in the United States. The FGF/FGFR1 signaling axis has been implicated in the progression of PCa. Different isoforms of FGFR1 have been described in PCa (e.g., alpha and beta), which might account for the typical heterogeneity of PCa. The isoforms may also mediate different clinical responses to treatments targeting this pathway. Pan-FGFR tyrosine kinase inhibitor JNJ-42756493 (Janssen) has been demonstrated to have antiproliferative effects in FGFR pathway-activated cancer cell lines and in vivo mouse antitumor activity. Our goal was to study the effects of JNJ-42756493 in PCa growth and signaling in vitro and establish whether these effects differ according to the FGFR1 isoform (alpha or beta) expressed. Using transfected bone-derived PCa cell lines and patient-derived xenografts (PDXs), we measured the effects of FGFR1 expression on cell proliferation and activation of the FGFR1-pMAPK signaling pathway. We then performed drug treatment experiments on FGFR1-expressing sublines and high-FGFR1 PDXs and observed the response in FGFR1-pMAPK signaling pathway activation. Our results showed that FGFR1 isoforms alpha and beta trigger different biological effects (i.e., proliferation), possibly contributing to the heterogeneity of PCa. We found that targeting the tyrosine kinase domain of FGFR1 with JNJ-42756493 results in pMAPK inhibition in PCa sublines. These findings indicate that the presence of specific FGFR1 variants should be considered for treatment selection in advanced PCa. The results also suggest that FGFR1-pMAPK pathway blockade by JNJ-42756493 should be further studied as a strategy to guide the development of therapies to hinder PCa progression. Citation Format: Louise Medina Bengtsson, Estefania Labanca, Nora Navone. Tyrosine kinase inhibition of fibroblast growth factor receptor 1 in advanced prostate cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3748.
Abstract 6377: Curcumin analog GO-Y030 diminishes cancer stem cell population by inhibiting interaction of HSP70 with its substrates
Authors: Maya Suzuki, Yohei Yamamoto, Aki Nishijima, Hiroyuki Shibata, Yasufumi Omori
Journal: Cancer Research (2020)

Abstract It has been established that a cancer tissue contains, in general, a small subpopulation of cancer stem cells (CSCs) having tumor initiation capacity. Because CSCs are resistant to chemoradiotherapy and play important roles in cancer relapse and metastasis, strategies targeting CSCs are crucial for effective anticancer therapies. Curcumin (diferuloylmethane) isolated from the rhizome of the plant turmeric (Curcuma longa) is one of the most widely characterized phytochemicals and well known to suppress cancer cell proliferation, invasion, angiogenesis, and metastasis by regulating multiple cell signaling pathways. However, its bioavailability is limited due to poor absorption. To improve this disadvantage, Ohori et al. (Mol Cancer Ther 2006;5:2563-71.) synthesized a new curcumin analog GO-Y030 (1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one), which has an about 30-fold greater growth-inhibitory effect than curcumin. In the current study, we verified the potency of GO-Y030 to act against CSC population. We first discovered that GO-Y030 could dose-dependently suppress a sphere-forming ability in human HuH7 hepatocellular carcinoma and human PC3 prostatic carcinoma cell lines. Interestingly, the specific inhibitor of the stress-inducible heat shock protein (HSP) 70 (also called HSP72, HSP70-1, or HSPA1A) exhibited effects similar to GO-Y030, i.e., inhibition of CSC sphere formation and upregulation of HSP70 and HSP40 protein expression. As this result suggested that target molecules of GO-Y030 might be HSP70 and its co-chaperones such as HSP40, we next performed in vitro HSP70/HSP40-mediated refolding activity assay and revealed that GO-Y030 efficiently inhibited HSP70/HSP40 chaperone activity. Finally, performing the substrate-binding assay, we have proven that GO-Y030 reduces the substrate-recognition and binding activity of HSP70. HSPs are molecular chaperones that function to prevent denaturation or unfolding of client proteins when they are threatened by stress or high temperature. Since CSCs by nature adapt to oxidative stress, mitochondrial dysfunction, and endoplasmic reticulum stress by enhancing synthesis of protein-folding chaperones, the function of HSP70/HSP40 is important for the maintenance of CSC population. Our data suggest that GO-Y030 should impair stress tolerance in CSCs by inhibiting the interaction of HSP70 with substrate proteins and disrupting the function of HSP70/HSP40 and thus should finally contribute to reduction of CSC population. Citation Format: Maya Suzuki, Yohei Yamamoto, Aki Nishijima, Hiroyuki Shibata, Yasufumi Omori. Curcumin analog GO-Y030 diminishes cancer stem cell population by inhibiting interaction of HSP70 with its substrates [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6377.
Abstract 4053: Mucin 5ac as a potential therapeutic target for KRAS-driven lung adenocarcinoma
Authors: Walter V. Velasco Torrez, Shanshan Deng, Marco A. Ramos-Castaneda, Segundo W. Del Aguila-Soto, Seyed Moghaddam
Journal: Cancer Research (2020)

Abstract Lung cancer continues to be the leading cause of cancer death in the United States, with more than 140,000 deaths per year. One of the main types of lung cancer is non-small cell lung cancer with lung adenocarcinoma (LUAD) being the most prominent subtype and is mainly due to oncogenic mutations like KRAS, which offers limited and unsuccessful treatments. The mucus barrier produced by mucins, particularly Mucin 5ac (Muc5ac) which is mainly expressed by lung epithelial cells, is essential for airway homeostasis. However, its overproduction can promote respiratory diseases such as chronic obstructive pulmonary disease (COPD), which is known to increase the risk of lung cancer by 3-10 fold. We have previously shown that Muc5ac is commonly expressed in patients with KRAS-driven LUAD and is associated with poor prognosis. Additionally, we found that lack of Muc5ac (genetic deletion) in mice with LUAD either induced chemically by urethane or genetically engineered with mutant KRAS presented with significantly reduced tumor burden. Therefore, we sought a translational approach by inhibiting Muc5ac in our KRAS-driven lung cancer mutant mouse model using an antisense oligonucleotide (ASO) against Muc5ac and hypothesized that the administration of this drug would result in decreased Muc5ac mRNA expression and reduced tumor burden. This was tested by intrapharyngeal administration of either ASO (5mg/kg) or vehicle (saline) twice a week to a cohort of six-week-old KRASG12D mutant mice for a total duration of eight weeks. Our results showed a 5-fold decrease in Muc5ac mRNA expression and a 42% reduction in overall tumor burden when compared to age and sex matched control mice. Additionally, analysis of bronchoalveolar lavage fluid showed a predominance of macrophages with significant downregulation of the protumorigenic M2 type macrophage polarization markers Fizz1 and Arg1 as well as significant upregulation of TNF-a, which suggests a mechanism mediated by direct tumor cytotoxic activity or apoptosis associated with a reduction in macrophage mediated immunosuppressive tumor microenvironment. In conclusion, our study suggests that administration of Muc5ac ASO effectively inhibits mucin production and ameliorates tumor progression, which ultimately could provide insight in both treatments and prevention against KRAS-driven LUAD. Citation Format: Walter V. Velasco Torrez, Shanshan Deng, Marco A. Ramos-Castaneda, Segundo W. Del Aguila-Soto, Seyed Moghaddam. Mucin 5ac as a potential therapeutic target for KRAS-driven lung adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4053.
Doctors who ran hospital where rogue breast surgeon worked face GMC charges
Authors: Clare Dyer
Journal: BMJ (2020)

The former chief executive and medical director of the NHS trust where the breast surgeon Ian Paterson worked are facing allegations that they knew of serious concerns about his clinical practice but failed to tell the General Medical Council.

Mark Goldman, who was chief executive of Heart of England NHS Foundation Trust from 2001 to 2010, and Ian Cunliffe, who was medical director from 2007 to 2010, face charges over their conduct as managers, rarely brought against doctors by the GMC.

The case is not expected to be heard by a medical practitioners tribunal until well into next year. But last week their counsel Mark Sutton QC argued at a preliminary hearing that the GMC should …
Abstract 6036: The clinicopathological significance of nerves and NGF receptors in esophageal cancer
Authors: Nathan Griffin, Fangfang Gao, Phillip Jobling, Vanessa Wills, Marjorie M. Walker, Sam Faulkner, Hubert Hondermarck
Journal: Cancer Research (2020)

Abstract Recent developments in oncology have revealed that nerve outgrowth in the tumor microenvironment is essential to the progression of many human cancers. In esophageal cancer, the presence and role of nerves and is unclear. In this study, nerves were identified within the tumor microenvironment of esophageal cancer and were associated with the squamous subtype of the disease (p=0.044). Additionally, the surrounding or invasion of nerves by cancer cells (perineural invasion) was detected in 12% of esophageal cancers and was associated with poor patient survival (p=0.038). Nerves were found to express the TrkA and p75NTR receptors for nerve growth factor (NGF) and an association was observed between high production of NGF by cancer cells and the presence of nerves (p=0.022). In vitro, esophageal cancer cells were able to induce neurite outgrowth in PC12 neuronal cells and this neurotrophic activity was inhibited by anti-NGF blocking antibodies. In squamous cell carcinoma tissues, TrkA expression was found to be strongly increased in compared to both adenocarcinoma and normal oesophageal tissue (p&amp;lt;0.0001). The selective pharmacological inhibitor of NTRK1, GNF-5837, induced a decreased esophageal cancer cell proliferation, invasion and migration. Together, these data demonstrate that innervation is a significant feature in esophageal cancers that may be driven by cancer cell-released NGF. Therefore, this study reveals that interventions against the NGF-TrkA signaling pathway may have the potential to target cancer cells and inhibit cancer neurogenesis. Citation Format: Nathan Griffin, Fangfang Gao, Phillip Jobling, Vanessa Wills, Marjorie M. Walker, Sam Faulkner, Hubert Hondermarck. The clinicopathological significance of nerves and NGF receptors in esophageal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6036.