tbuckley/cabot-search huggingface dataset:
Abstract 3243: Allogeneic anti-PTK7 CAR-T cells for the treatment of solid tumors
Authors: Katie Levitsky, Zejun Li, Minh Thu Pham, Kelly Maeng, Luke Hanley, Jason Sagert, Jon Terrett, Jui Dutta-Simmons, Melanie Allen
Journal: Cancer Research (2020)

Abstract Protein Tyrosine Kinase 7 (PTK7), also known as colon cancer carcinoma kinase 4 (CCK-4), is a highly conserved catalytically inactive tyrosine kinase with inherent signal transduction activity. PTK7 is a member of the Wnt signaling pathway and thought to function in cell proliferation, adhesion, migration and apoptosis. PTK7 has been shown to be highly expressed in certain cancer types including colon, breast, lung, pancreatic, renal and ovarian. Downregulation of PTK7 by shRNA has been shown to reduce tumor growth and metastases development in xenograft mouse models. Furthermore, high PTK7 expression in triple negative breast cancer and NSCLC patients has been linked to poor prognosis. PTK7 therefore appears to be an attractive target for solid cancer therapeutic intervention and has been targeted clinically with an Antibody Drug Conjugate (PF-06647020). However, the protein is also expressed to a lesser degree in some normal adult tissues, particularly in the stromal cells of the ovary, placenta, uterus and lung. We have developed a human/murine cross-reactive anti-PTK7 CAR construct and assessed the ability of allogeneic anti-PTK7 CAR-T cells bearing that construct to target cancer cells and elicit toxicity in mice. These anti-PTK7 CAR-T cells were shown to be efficacious in vitro and in immunocompromised mouse xenograft models of breast, lung, colon, pancreatic and ovarian cancer. However, consistent in all xenograft models studied, a drop in body weight was observed shortly after injection from which all mice rapidly recovered to above baseline. Latent toxicity that was more variable amongst the xenograft experiments was also observed. Understanding and developing appropriate mitigation strategies to address the observed toxicities may be required to develop further a safe and efficacious allogeneic anti-PTK7 CAR-T cell therapy for solid tumor cancers. Citation Format: Katie Levitsky, Zejun Li, Minh Thu Pham, Kelly Maeng, Luke Hanley, Jason Sagert, Jon Terrett, Jui Dutta-Simmons, Melanie Allen. Allogeneic anti-PTK7 CAR-T cells for the treatment of solid tumors [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 3243.
Abstract 3298: Eosinophilia and improved survival in non-hematologic malignancies treated with immune checkpoint inhibitors
Authors: Jasmine L. Mitchell, Justin Moyers, Huynh Cao
Journal: Cancer Research (2020)

Abstract Background Immune checkpoint inhibitors (ICI) have become a mainstay treatment of a variety of advanced malignancies, prolonging survival. There are no serologic markers to predict response to ICI, but some small series have suggested eosinophilia predicts improved survival. Methods This is an IRB approved single-center retrospective observational study including all patients (n= 80) from 2014-2019 who received ICI for non-hematologic malignancies at Loma Linda University Medical Center. Data were collected via chart review. Clinically significant increase of absolute eosinophil count was defined as a count &amp;gt; 0.5 bil/L on at least two occasions during treatment. Kaplan-Meier survival estimates were used to estimate overall survival. Results In non-small cell lung cancer (n= 35), patients with eosinophilia (n=5) had no death events compared to the median survival of 17.6 months in those without eosinophilia (p = 0.02). Similarly, in patients with renal cell carcinoma (n=11), those with eosinophilia (n=2) had no death events while the median survival for those without was 16.9 months (p= 0.24). In the metastatic melanoma cohort (n=9), those with eosinophilia (n= 5) had a median overall survival of 45.4 vs 9.9 months in those without (p= 0.02). Conclusions In both NSCLC and metastatic melanoma, eosinophilia during ICI therapy was associated with significantly increased overall survival, while in RCC there was a trend towards improved survival. Interestingly, there were no death events in those with eosinophilia in either NSCLC or RCC cohorts. Citation Format: Jasmine L. Mitchell, Justin Moyers, Huynh Cao. Eosinophilia and improved survival in non-hematologic malignancies treated with immune checkpoint inhibitors [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 3298.
Circulating T-cell Immunosenescence in Patients with Advanced Non–small Cell Lung Cancer Treated with Single-agent PD-1/PD-L1 Inhibitors or Platinum-based Chemotherapy
Authors: Roberto Ferrara, Marie Naigeon, Edouard Auclin, Boris Duchemann, Lydie Cassard, Jean-Mehdi Jouniaux, Lisa Boselli, Jonathan Grivel, Aude Desnoyer, Laura Mezquita, Matthieu Texier, Caroline Caramella, Lizza Hendriks, David Planchard, Jordi Remon, Sabina Sangaletti, Claudia Proto, Marina C. Garassino, Jean-Charles Soria, Aurelien Marabelle, Anne-Laure Voisin, Siham Farhane, Benjamin Besse, Nathalie Chaput
Journal: Clinical Cancer Research (2020)

CD28, CD57, and KLRG1 have been previously identified as markers of T-cell immunosenescence. The impact of immunosenescence on anti-PD(L)-1 (ICI) or platinum-based chemotherapy (PCT) in patients with advanced non-small cell lung cancer (aNSCLC) is unknown.The percentage of CD28-, CD57+, KLRG1+ among CD8+ T cells [senescent immune phenotype (SIP)] was assessed by flow cytometry on blood from patients with aNSCLC before single-agent ICI (discovery cohort). A SIP cut-off was identified by log-rank maximization method and patients with aNSCLC treated with ICI (validation cohort) or PCT were classified accordingly. Proliferation and functional properties of SIP+ CD8+ T cells were assessed in vitro.In the ICI discovery cohort (N = 37), SIP cut-off was 39.5%, 27% of patients were SIP+. In the ICI validation cohort (N = 46), SIP+ status was found in 28% of patients and significantly correlated with worse objective response rate (ORR; 0% vs. 30%, P = 0.04), median progression-free survival (PFS) [1.8 (95% confidence interval (CI), 1.3-NR) vs. 6.4 (95% CI, 2-19) months, P = 0.009] and median overall survival, OS [2.8 (95% CI, 2.0-NR) vs. 20.8 (95% CI, 6.0-NR) months, P = 0.02]. SIP+ status was significantly associated with circulating specific immunephenotypes, in vitro lower CD8+ T cells proliferation, lower IL2 and higher TNFα and IFNγ production. In the ICI-pooled population (N = 83), SIP+ status did not correlate with any clinical characteristics and it was associated with significantly worse ORR, PFS, and OS. In PCT cohort (N = 61), 11% of patients were SIP+. SIP status did not correlate with outcomes upon PCT.Circulating T-cell immunosenescence is observed in up to 28% of patients with aNSCLC and correlates with lack of benefit from ICI but not from PCT.See related commentary by Salas-Benito et al., p. 374.
Abstract 1887: Tumor-stroma interactions mediated by Semaphorin 6A as a determinant of drug resistance in BRAF-mut melanoma
Authors: Rossella Loria, Italia Falcone, Marta Di Martile, Valentina Caprara, Rocco Fraioli, Valentina Laquintana, Giulia Bon, Laura Rosanò, Donatella Del Bufalo, Ludovica Ciuffreda, Virginia Ferraresi, Michele Milella, Rita Falcioni
Journal: Cancer Research (2020)

Abstract In BRAF-mutant (BRAF-mut) melanoma combined BRAF/MEK inhibition increases survival. However, pharmacological effects on the genetically “normal” tumor microenvironment (i.e. paradox MAPK activation) may set the stage for the development of drug resistance. In melanoma specimens, we observed a significant correlation between BRAF-mut and the expression of Semaphorin 6A (Sema6A), a member of the semaphorin family that regulates actin cytoskeleton remodeling, motility and cell proliferation. In BRAF-mut melanoma cell lines, Sema6A is involved in cytoskeleton remodeling by regulation of YAP activity. Sema6A depletion induced a decrease in RhoA activation and, consequently, an increase in phospho-YAP and a reduction in cell proliferation rate. We thus hypothesized that actin cytoskeleton remodeling and dynamic evolutions may play a role in both cell autonomous and stroma-mediated mechanisms of drug-resistance in this context. To assess the functional relevance of Sema6A expression in the regulation of melanoma/stroma interactions and sensitivity/resistance to pathway inhibitors, we performed an inducible Sema6A knock down in BRAF-mut melanoma cell lines and evaluated the response to BRAF/MEK inhibitors in monolayer and 2D co-culture systems. In contexts of partial response or resistance in vitro, BRAF inhibitors, alone or combined with MEK inhibitors, were increased Sema6A expression at the mRNA and protein levels in both monolayer and 2D co-culture systems. Furthermore, Sema6A silencing performed in 2D co-culture system abrogated the protective effect of melanoma/stroma interactions, resulting in a synergistic effect with BRAF/MEK inhibitors. Overall, our results suggest that Sema6A could be a crucial mediator of protective tumor/stroma interactions, involved in resistance to MAPK inhibition in melanoma. Citation Format: Rossella Loria, Italia Falcone, Marta Di Martile, Valentina Caprara, Rocco Fraioli, Valentina Laquintana, Giulia Bon, Laura Rosanò, Donatella Del Bufalo, Ludovica Ciuffreda, Virginia Ferraresi, Michele Milella, Rita Falcioni. Tumor-stroma interactions mediated by Semaphorin 6A as a determinant of drug resistance in BRAF-mut melanoma [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 1887.
Abstract 5324: Structure-based design of CDC42/RHOJ effector inhibitors for the treatment of cancer
Authors: Jessica L. Flesher, Sohail Jahid, Jose A. Ortega, Giuseppina La Sala, Nicoletta Brindani, Jose M. Arencibia, Jacopo Manigrasso, Stephanie Hachey, Chi-Fen Chen, Chris Hughes, Marco De Vivo, Anand K. Ganesan
Journal: Cancer Research (2020)

Abstract The CDC42 family of GTPases (RHOJ, RHOQ, CDC42) control both the ability of tumor cells to invade surrounding tissues and the ability of endothelial cells to vascularize tumors. While recent studies have developed small molecules that target RAS GTPases, little progress has been made in targeting the related CDC42 family of GTPases for cancer treatment. Here, we use computer-aided drug design to identify a novel class of inhibitors that act on an allosteric pocket in the active form of the CDC42 GTPase, RHOJ. These allosteric inhibitors prevent RHOJ and CDC42 from binding to their downstream effector PAK, while having no effect on the interactions between the closely related GTPase RAC1 and PAK or RAS and its downstream effector RAF. Our lead compound ARN22089 has a druglike profile and can block both tumor growth and tumor angiogenesis in a three-dimensional vascularized microtumor (VMT) model, indicating that ARN22089 blocks RHOJ/CDC42 signaling in both the tumor cell and the tumor endothelium. Short term treatment of nascent melanoma tumors with ARN22089 halted the growth of BRAF mutant autochthonous mouse melanoma tumors, slowed the growth of melanoma patient-derived xenografts, and induced tumor necrosis in PDX models. In summary, we describe a multidisciplinary structure-based drug discovery platform that can identify new RHO family allosteric inhibitors and use this system to identify RHOJ inhibitors that block tumor growth in vivo. Citation Format: Jessica L. Flesher, Sohail Jahid, Jose A. Ortega, Giuseppina La Sala, Nicoletta Brindani, Jose M. Arencibia, Jacopo Manigrasso, Stephanie Hachey, Chi-Fen Chen, Chris Hughes, Marco De Vivo, Anand K. Ganesan. Structure-based design of CDC42/RHOJ effector inhibitors for the treatment of 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 5324.
Abstract 6513: 3,3'-diindolylmethane enhances tumor regression after radiation through protecting normal cells to modulate anti-tumor immunity
Authors: Renxiang Chen, Lijun Li, Yun-Tien Lin, Arslon Humayun, Albert J. Fornace, Heng-Hong Li
Journal: Cancer Research (2020)

Abstract Preclinical and clinical data indicate that radiotherapy acts as an immune modifier, having both immunostimulatory and immunosuppressive effects on the tumor immune microenvironment (TIME). 3.3'-Diindolylmethane (DIM), the acid-catalyzed dimer of the bioactive indole found in cruciferous vegetables, has long been known for its anticancer properties and has been proposed for use as a cancer prevention agent. The current study characterizes how DIM influences TIME and tumor regression after fractionated radiation treatment using preclinical breast cancer models. We first compared tumor graft models using immune-competent and immune-deficient mouse strains to find out whether immune cells are required for DIM's effects. Tumor targeted radiation was done using narrow-beam radiation with shielding. Tumor regression was monitored after DIM and radiation combined treatment and radiation alone. Our results indicated that DIM enhanced tumor regression after radiation treatment in immune-competent but not immuno-deficient mice. Data from nCounter® PanCancer immune profiling panel showed DIM increased intratumoral immune cells including cytotoxic T cells, neutrophils and macrophages after radiation and enhanced immunological processes such as adhesion and antigen processing. Expression of several MHC Class II molecules and CD74, a gene encoding chaperone and transport cofactor that assists MHC II molecules folding and presenting, significantly increased in the combined treatment of radiation and DIM. The results showing that DIM treatment alone does not affect tumor growth suggested that DIM's radioprotective effect on non-tumoral cells, including stromal cells and immune cells, plays a critical role in promoting a microenvironment that favors anti-tumor immunity. Additional experiments showed that DIM protected normal cells from radiation-caused immediate injuries in vitro and in vivo. In summary, DIM's radioprotective effects on immune cells and other normal cells are important in promoting a TIME that favors anti-tumor immunity. As a result, DIM increases the efficacy of radiation treatment on tumor regression. This study supports the development of DIM as an adjunct agent for radiation treatment. Citation Format: Renxiang Chen, Lijun Li, Yun-Tien Lin, Arslon Humayun, Albert J. Fornace Jr., Heng-Hong Li. 3,3'-diindolylmethane enhances tumor regression after radiation through protecting normal cells to modulate anti-tumor immunity [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 6513.
Abstract 824: Uncommon EGFR mutations are associated with higher tumor mutation burden (TMB) in non-small cell lung cancer patients
Authors: Xudong Shen, Hushan Zhang, Depei Huang
Journal: Cancer Research (2020)

Abstract Background: Epidermal growth factor receptor (EGFR) mutation is regarded as a predictor for poor clinical response to immunotherapy in non-small cell lung cancer (NSCLC), for which common EGFR mutations (the L858R point mutation and exon 19 deletions) generally exist lower tumor mutation burden (TMB) level. On the other side, uncommon EGFR mutations exist variable efficacy to tyrosine kinase inhibitors (TKIs) and the treatment for these patients is still controversial. Therefore, we conducted this study to investigate the correlation between uncommon EGFR mutations and TMB. Methods: The tissue samples from a Chinese cohort of 2177 lung adenocarcinoma (LAC) and 500 lung squamous cell carcinoma (LSCC) patients were detected by a 381 genes NGS panel from 3D Medicines, and TMB values were obtained from the NGS sequencing data. We evaluated the correlation between common and uncommon mutations in EGFR and TMB in lung adenocarcinoma and squamous cell carcinoma, respectively. Results: In lung adenocarcinoma, patients with uncommon EGFR mutations (n = 208) had a higher TMB level compared with common EGFR mutations (n = 1027) (medium TMB 6.14 Muts/Mb vs 4.84 Muts/Mb, P = 0.0016), but a lower TMB level than patients without EGFR mutations (n = 942) (medium TMB 6.14 Muts/Mb vs 7.26 Muts/Mb, P = 0.0176). In lung squamous cell carcinoma, the TMB level of uncommon EGFR mutations (n = 21) was significantly higher than common EGFR mutations (n = 20) (medium TMB 12.90 Muts/Mb vs 5.40 Muts/Mb, P &amp;lt; 0.0001). Meanwhile, the medium value of TMB in uncommon mutations group was slightly higher than non-mutations group (n = 459), however, there was no significant difference between the two groups (medium TMB 12.90 Muts/Mb vs 11.29 Muts/Mb, P = 0.2186). Conclusions: Uncommon mutations in EGFR are associated with higher TMB level than common mutations in both lung adenocarcinoma and squamous cell carcinoma. Citation Format: Xudong Shen, Hushan Zhang, Depei Huang. Uncommon EGFR mutations are associated with higher tumor mutation burden (TMB) in non-small cell lung cancer patients [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 824.
Abstract 4170: Decursin inhibits gastric cancer cell growth and autophagic flux by suppressing cathepsin C
Authors: Solbi Kim, Mina Joo, Nayoung KIM, Myung-Won Lee, Heung Jin Jeon, Hyewon Ryu, Ik-Chan Song, Hyo Jin Lee
Journal: Cancer Research (2020)

Abstract Purpose: Autophagy is a series of processes in which biomolecules are digested and recycled, and it also provides energy for the development and progression of cancer. Thus, autophagy inhibitors can be used to suppress the progression of cancer. In this study, we investigated whether decursin, which is derived from natural products, inhibits the growth and autophagy of cancer cells. Methods: The gastric cancer cell lines SNU216 and NCI-N87 were treated with or without decursin. Cell growth was evaluated by Cell-Counting Kit-8, colony formation, and BrdU assays, as well as by propidium iodide staining, and autophagic flux was evaluated by western blotting, LC3 puncta, GFP-RFP-LC3, and transmission electron microscopy. Finally, tumor spheroids and patient-derived gastric cancer organoids were used to confirm the effect of decursin in three-dimensional culture. Results: Decursin reduced the growth and anchorage-dependent viability of gastric cancer cells. LC3 cleavage and LC3-GFP puncta were increased by decursin in a time- and concentration-dependent manner. However, the increase in autophagosome formation did not lead to an increase in autophagic flux. Decursin downregulated cathepsin C (CTSC), a lysosomal protease, irrespective of cellular pH. In addition, knockdown of CTSC reduced the mRNA and protein levels of E2F3, resulting in cell-cycle arrest. Decursin also reduced cell growth in both tumor spheroids and patient-derived gastric cancer organoids. Conclusion: The results demonstrated that decursin inhibited tumor growth and progression by suppressing CTSC-mediated autophagic flux and cell-cycle progression. Therefore, decursin is a novel inhibitor of autophagic flux, with potential for the treatment of gastric cancer. Citation Format: Solbi Kim, Mina Joo, Nayoung KIM, Myung-Won Lee, Heung Jin Jeon, Hyewon Ryu, Ik-Chan Song, Hyo Jin Lee. Decursin inhibits gastric cancer cell growth and autophagic flux by suppressing cathepsin C [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 4170.
Abstract 4831: Stability of draw-time microRNA concentration in blood collection tubes
Authors: Eunju Seong, Nicholas M. George
Journal: Cancer Research (2020)

Abstract Plasma microRNA, which is relatively abundant compared to other extracellular RNA species, has drawn attention for its potential implication as biomarkers of various disease conditions. However, the great donor-to-donor variability of specific microRNA levels has been a challenging factor in their further development as a diagnostic biomarker assay. Also widely recognized, the levels of specific microRNAs are sensitive to sample collection, storage and extraction methods. Upon blood draw, the plasma microRNAome undergoes changes in concentration as well as in composition, mostly due to the in vitro blood cell breakdown. In this study, using different blood collection tubes including EDTA and Streck RNA Complete BCT, we compared microRNA extraction from the full plasma vs from isolated plasma exosomes. For each sample, we measured microRNA concentrations by global fluorometric assays and by quantitative PCR for specific microRNAs. The Streck tube minimizes the in vitro changes of microRNAome, thus facilitating detection of rare microRNAs originating from a distant diseased tissue. Citation Format: Eunju Seong, Nicholas M. George. Stability of draw-time microRNA concentration in blood collection tubes [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 4831.
Abstract 2371: FBXL12 modulates Fanconi anaemia-BRCA signaling under conditions of oncogene-induced replication stress
Authors: Andrä Brunner, Henrik Johansson, Alexandros Kourtesakis, Juha Rantala, Charles Spruck, James Wohlschlegel, Janne Lehtiö, Olle Sangfelt
Journal: Cancer Research (2020)

Abstract Oncogene-induced replication stress (OIRS) constitutes an early obstacle to cancer progression. De-regulation of cell death or senescence programs contribute to overcoming this barrier. However, even after escaping these fail-safe mechanisms, cancer cells need to handle elevated levels of DNA damage and ensuing genomic instability in order to continue proliferating. How this is achieved is only partially understood. To advance our understanding of this response and to identify potentially druggable regulators, we screened the family of human F-box proteins (FBP) for effects on replication re-start under conditions of OIRS. FBPs function as interchangeable substrate recognition sub-units of the SKP1-Cullin1-FBP ubiquitin ligase complex. They are required for conferring substrate specificity to the complex and some FBPs have been attributed roles as oncogenes or tumor suppressors while the majority remain largely uncharacterized. Our screen revealed the relatively unknown FBP FBXL12 as crucial regulator for sustained proliferation and genomic integrity under conditions of cyclin E-induced replication stress. FBXL12-depleted cells exhibit excessive replication fork stalling, high levels of DNA damage signaling and spontaneous senescence in OIRS breast cancer model cell lines. Interestingly, the same effects are not manifest in untransformed cell lines. Furthermore, we found that FBXL12 interacts with central chromatin-associated components of the Fanconi anemia (FA)-BRCA signaling pathway, ubiquitylating and targeting them for proteasomal degradation, and thereby exerting its effects on stalled replication forks. The specific nature of FA-BRCA signaling regulation by FBXL12 as well as potential clinical implications for basal-like breast cancers will be discussed. Citation Format: Andrä Brunner, Henrik Johansson, Alexandros Kourtesakis, Juha Rantala, Charles Spruck, James Wohlschlegel, Janne Lehtiö, Olle Sangfelt. FBXL12 modulates Fanconi anaemia-BRCA signaling under conditions of oncogene-induced replication stress [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 2371.