tbuckley/cabot-search huggingface dataset:
Abstract 5280: Kinase fusions drive endocrine resistance in estrogen receptor-positive breast cancer
Authors: Bo Liu, Dara S. Ross, Alison M. Schram, Pedram Razavi, Stephen M. Lagana, Yanming Zhang, Maurizio Scaltriti, Jacqueline F. Bromberg, Marc Ladanyi, David M. Hyman, Alexander Drilon, Ahmet Zahir, Ryma Benayed, Jaclyn F. Hechtman, Sarat Chandarlapaty
Journal: Cancer Research (2020)

Abstract Oncogenic kinase activation by gene fusions can promote cancer development and tumor progression, however, kinase fusions have not been characterized extensively in breast cancer. In this study, we characterized kinase fusions in a large cohort of 4854 breast cancer patients using clinical DNA and/or RNA next generation sequencing platforms. Twenty-seven cases harboring kinase fusions were identified, including 11 FGFR (5 FGFR2, 3 FGFR3, 3 FGFR1), 5 BRAF, 4 NTRK1, 2 RET, 2 ROS1, 1 ALK, 1 ERBB2, and 1 MET. Eight patients with a history of endocrine therapy had available pre-treatment samples, of which six were negative for kinase fusion, and ESR1 hotspot mutations were not observed in any of these kinase fusion-positive samples. These findings suggest a potential role for kinase fusions in endocrine therapy resistance and prompted us to model the kinase fusions in human breast cancer cell lines. Ectopic expression of LMNA-NTRK1 fusion kinase activated growth factor signaling cascades, including PI3K-AKT and MAPK-ERK pathways, and promoted hormone-independent growth in MCF7 and T47D cells. Enforced expression of the LMNA-NTRK1 fusion conferred resistance to the ER antagonist fulvestrant and combined treatment of fulvestrant and the Trk inhibitor larotrectinib completely blocked the growth of LMNA-NTRK+ breast cancer cells. Similarly, expression of the EML4-ALK fusion also activated growth factor signaling pathways and caused resistance to estrogen depletion and induced sensitivity to the ALK inhibitor, Ceritinib. Treatment of xenografted LMNA-NTRK1 expressing tumors confirmed the efficacy of the combined treatment of antiestrogen and NTRK1 inhibition in vivo. Two patients with acquired LMNA-NTRK1 fusions and metastatic disease received larotrectinib and demonstrated clinical benefit. Overall, our findings demonstrate that kinase fusions promote endocrine resistance in ER-positive breast cancer, and suggest that fusion screening in advanced breast cancer, particularly those with ER-positive breast cancer at progression on hormone therapy can identify rare tumors harboring targetable kinase fusions. Citation Format: Bo Liu, Dara S. Ross, Alison M. Schram, Pedram Razavi, Stephen M. Lagana, Yanming Zhang, Maurizio Scaltriti, Jacqueline F. Bromberg, Marc Ladanyi, David M. Hyman, Alexander Drilon, Ahmet Zahir, Ryma Benayed, Jaclyn F. Hechtman, Sarat Chandarlapaty. Kinase fusions drive endocrine resistance in estrogen receptor-positive breast 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 5280.
PF627 SERUM CEREBLON LEVELS PREDICT FIVE‐ YEAR POST LEALIDOMIDE/DEXAMETHASONE (RD) SURVIVAL IN MULTIPLE MYELOMA (MM) PATIENTS AND CORRELATE WITH DISEASE CHARACTERISTICS
Authors: A.I. Gkioka, P. Papaioannou, None Tryfou?., R. Niki, M. Dimou, I. Theodoros, V. Pardalis, A. Bitsani, A. Koudouna, I. Grafakos, P. Panayiotidis, M.‐C. Kyrtsonis
Journal: HemaSphere (2019)

Background: Cereblon (CRBN) was identified as target protein of Immunomodulatory Drugs (ImiDs). It was shown that its decreased expression was related to ImiDs resistance and carcinogenesis. However, very little is known about the importance of serum CRBN concentrations. Aims: To determine serum CRBN in MM patients treated with RD (lenalidomide‐dexamethasone) and to study eventual correlations with disease characteristics. Methods: We studied 91 MM patients from RD initiation until last follow up or death; their files were reviewed after patients’ informed consent was obtained, while clinical and laboratory characteristics were collected. Frozen patients’ sera, drawn at the time of RD treatment (68 patients), best response (59 patients) and at relapse/refractoriness to Rd (54 patients) were retrospectively analyzed. CRBN was measured by commercially available ELISA kit (cloud clone), according to the manufacturer's instructions. Twenty healthy individuals (HI) were also tested. Statistical analysis was performed using the SPSS v24.0. software. Results: The median age of patients was 70 years (56% men, 44% women). Ig type was IgG in 64%, IgA in 22%, light‐chain in 11% and IgD or biclonal in 3%. Thirty percent of patients were staged ISS 1, 20% ISS 2 and 51% ISS 3. RD was administered in 1 st line in 8% of patients, second in 37%, third in 26%, forth in 16% and in 5 th to 9 th line in 13%. Median serum CRBN levels at RD initiation were 247 pg/ml (0–9760), 148,8 pg/ml (0 ‐9940) at best response and 294 pg/ml (0–9840) at relapse/resistance to RD. In HI CRBN ranged from 0 to 580 pg/ml. CRBN values at RD initiation were negatively correlated with paraprotein levels (τ = −0,204, p = 0,05). At best response they marginally correlated with quality of response (τ = −0,250, p = 0,055). Median serum CRBN level was used as a cut‐off point in survival analysis. Median overall survival was 70 months (range, 7–345) and time until next treatment was 14 months (range, 1–110). Five‐year survival was improved in patients with CRBN levels below median at the time of RD initiation (p = 0,03), during best response (p = 0,035), and in relapse/refractory patients to Rd (p = 0,05) while time to next treatment was significantly shorter in patients with CRBN levels above median at best response (p = 0,026). Summary/Conclusion: serum CRBN levels below median were related to a better 5‐year survival post RD and to time to next treatment. Mechanisms leading to protein release in the serum possibly explain this apparent discrepancy with the reported impact of low CRBN expression.
Abstract 1247: NOX4 P62 regulates tuberculous fibrosis promoted tumorigenic potential
Authors: Yoonki Hong, Seong-Ji Woo, Youngmi Kim, Ji Young Hong
Journal: Cancer Research (2020)

Abstract Background Increased incidence of lung cancer in subjects with previous tuberculous infection was reported in epidemiologic data. NOX4 signaling contributes to tuberculous pleural fibrosis and lung cancer proliferation, respectively. The objective of this study was to investigate the role of NOX4 in tuberculous pleurisy-assisted tumorigenicity both in vitro and in vivo. Methods After pleural mesothelial cells from WT and NOX4 KO C57BL/6 mice were stimulated with Heat-Killed mycobacterium tuberculosis (HKMT) for 24 hour, cellular interactions between mesothelial cell and cancer cell were evaluated by using transwell invasion assay and wound healing assay. A murine model injected with cancer at 4 weeks after Mycobacterium bovis bacillus Calmette-Guérin (BCG) pleural infection were used to validate the contribution of tuberculous fibrosis to tumor invasion. Results HKMT -stimulated mesothelial cells induced enhanced invasion and migration potential of lung cancer cells in a NOX4-dependent manner. The inhibition of NOX4 signaling exerted a negative effect on the metastatic potential of lung cancer by tuberculous fibrosis in mice model. The expression of inflammatory cytokines like TNF-a, TGF-β and IL-6 was enhanced in the WT-BCG+CA than WT+PBS+CA and NOX4 KO+BCG+CA. The expression of P62 in lung tissue was higher in the WT-BCG+CA than WT+PBS+CA and NOX4 KO+BCG+CA. Discussions Our results suggest that NOX4 and autophagy signaling changed by tuberculous fibrosis could result enhanced tumorigenic potential. NOX4-P62 might seve as a target for the development of anti-tuberculous fibrosis and anti-cancer drugs. Citation Format: Yoonki Hong, Seong-Ji Woo, Youngmi Kim, Ji Young Hong. NOX4 P62 regulates tuberculous fibrosis promoted tumorigenic 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 1247.
Abstract 1608: Adaptive resistance to PD-1 blockade upregulates Tim-3 through STAT3 pathway in regulatory T cells in melanoma
Authors: Lili Huang, Yu Xu, Juemin Fang, Weixing Liu, Zhuqing Liu, Qing Xu
Journal: Cancer Research (2020)

Abstract Tregs play an opposing role in anti-tumour immunity by suppressing effective immunotherapies in melanoma. Thus, understanding the precise mechanisms of Tregs in immune therapy is important. TILs separated from freshly excised melanoma tumours and PBMCs obtained from healthy donors were used to assess the expression levels of Tim-3 and IL-10/TGF-β of Tregs by multi-colour flow cytometry and immunohistochemistry in the presence or absence of an anti-PD-1 antibody or STAT3 inhibitor in vitro and in vivo. The mRNA level of STAT3 gene was closely associated with the expression of PD-1 and Tim-3 in melanoma patients. Tim-3 expression was significantly upregulated on Tregs after PD-1 blockade in mice treated with either induced mouse and human melanoma TILs or healthy donor PBMCs. The levels of IL-10 and TGF-β secretion in the TIL group increased compared with those in the control group, supporting a potential escape mechanism from anti-PD-1 therapy in the tumour microenvironment. Furthermore, in the presence of the STAT3 pathway inhibitor Stattic, Tim-3 and PD-1 expression on Treg was regulated on TILs from respondent mice melanoma, suggesting that STAT3 could mediate Tim-3 and PD-1 expression on Treg in tumor microenvironment. Therefore, our findings reveal the mechanism of PD-1 and Tim-3 expression in a STAT3-dependent manner on Tregs in the TME, providing further support for STAT3 as a potential transient small molecular inhibitor targets for patients suffering from melanoma. Citation Format: Lili Huang, Yu Xu, Juemin Fang, Weixing Liu, Zhuqing Liu, Qing Xu. Adaptive resistance to PD-1 blockade upregulates Tim-3 through STAT3 pathway in regulatory T cells in 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 1608.
Abstract 2274: Development of bispecific antibodies using molecular imaging
Authors: Daisuke Kamakura, Masahiro Yasunaga, Ryutaro Asano, Yasuhiro Matsumura
Journal: Cancer Research (2020)

Abstract (Background and purpose) A bispecific antibody (BsAb), as a next-generation therapeutic antibody, has two antigen binding sites in an antibody molecule. Many formats have been exploited for decades. Among them, we focused on T cell dependent BsAb (TDB), which can engage and redirect cytotoxic T cells against tumor cells and is expected to be effective in treating refractory cancer. However, although many studies revealed its potent antitumor effect in animal models, it has not been applied to solid tumors yet in clinics. In this context, we think that it is necessary to clarify pharmacokinetics (PK), pharmacodynamics (PD) and mechanism of action (MOA) of TDB, especially within tumor tissue. For this aim, we have decided to develop the molecular imaging-based systems for the evaluation of TDB in order to visualize antigen binding to two target antigens, BsAb delivery or immunological synapse formation. (Materials a&amp; Methods) We used hEx3 which is a humanized IgG-like antibody with bivalent Fv regions against each EGFR and CD3. We applied the TDB to colorectal cancer (CRC) cells with or without KRAS or BRAF mutation. In the first part, we visualized the BsAb binding to two antigens, EGFR on CRC cells and CD3 on T cells. Next, immunological synapse formation as a cutting-edge mechanism involving T cells-killing tumor cells, which is an important MOA of TDB, was visualized in combination with Granzyme staining. In the second part, we evaluated in vitro cytotoxicity and the in vivo antitumor effect of hEx3 in NOD-SCID mice bearing CRC xenografts with KRAS or BRAF mutation following human PBMC administration. (Results) We found that CRC cells were damaged via Granzyme accumulation through immunological synapse. In the ELISA data, we also found that released gamma interferons can damage CRC cells. In vitro and In vivo studies showed that the hEx3 demonstrated a significant cytocidal effect and antitumor activity not only for KRAS wild but also mutant. (Conclusion) we established a molecular imaging-based TDB evaluation system and visualized antigen-binding and immunological synapse formation as a MOA of TDB. Present data indicated that TDB can damage CRC cells in two distinct manners, namely immunological synapse-dependent and -independent manners using cytokines including a gamma interferon. TDB may thus be a promising next generation antibody therapy against CRC regardless KRAS status. Citation Format: Daisuke Kamakura, Masahiro Yasunaga, Ryutaro Asano, Yasuhiro Matsumura. Development of bispecific antibodies using molecular imaging [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 2274.
Abstract 322: A unique <i>ex vivo</i> tumor model: 3D co-cultured system with cancer cells and stromal tissue for drug evaluation
Authors: Yuki Takahashi, Kei Tsukamoto, Yuki Shimizu, Ryohei Katayama, Eiji Shinozaki, Satoshi Nagayama, Michiya Matsusaki, Shiro Kitano, Kensei Yamaguchi, Naoya Fujita
Journal: Cancer Research (2020)

Abstract Background;Recently, three-dimensional culture model has been reported as better tumor model than 2D culture. The importance of interaction between cancer and stromal cells has been widely recognized in tumor progression and resistance against treatment. So that ex vivo model which recaptures the tumor microenvironment is required to perform drug evaluation mimicking the patient tumor tissue. Methods; Layered 3D stromal tissues with microvascular network were produced by culturing normal fibroblasts and endothelial cells coated with the extra-cellular matrix (ECM) and natural polysaccharide, namely collagen and heparin. The layered 3D stromal tissues and co-cultured tumor were morphologically evaluated by HE staining, immunohistochemistry and immunofluorescence (IF). Drug sensitivity assay were conducted using popular colorectal cancer cell lines, and patient-derived cell lines (PDCs) established in JFCR under approved IRB. Remaining cancer cells post drug treatment were quantified by IF and imaging analysis. Furthermore, in vivo drug sensitivity was also evaluated. Results: The CD31 positive luminal structures which shows vascular endothelial tube formation were observed intra multi-layered tissues. The dense microvascular network tended to be formed nearby cancer cells. In comparison with 2D culture model, decreased drug sensitivities were represented in the layered 3D co-cultured model. The evaluated drug sensitivities in 3D model may reflect the response of cancer cells in in vivo. Conclusion; We developed the layered 3D stromal tissue culture system including blood micro-vessels. Our unique 3D ex vivo model appear to be a valuable tool for drug evaluation, and thus further studies are underway to confirm the usefulness of our model. Testing approved and/or developing compounds with PDCs in the model would potentially enable better prediction their efficacy. Citation Format: Yuki Takahashi, Kei Tsukamoto, Yuki Shimizu, Ryohei Katayama, Eiji Shinozaki, Satoshi Nagayama, Michiya Matsusaki, Shiro Kitano, Kensei Yamaguchi, Naoya Fujita. A unique ex vivo tumor model: 3D co-cultured system with cancer cells and stromal tissue for drug evaluation [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 322.
Abstract LB-052: Photochemistry mediated tumor priming potentiates cytoreduction of distant metastases to enable potential surgical cure in a late stage model of pancreas cancer
Authors: Sriram Anbil, Zhiming Mai, Michael Pigula, Tayyaba Hasan
Journal: Cancer Research (2020)

Abstract Pancreatic cancer is a devastating disease for which the 5 year survival rate remains &amp;lt; 10% despite years of concerted research efforts. Potentially curative surgical resection cannot even be offered to most patients due to the presence of distant metastases at the time of diagnosis. Here, we present a neoadjuvant strategy comprised of photochemistry mediated tumor modulation combined with systemic therapy to significantly cytoreduce, and in 50% of cases completely eliminate, distant metastases to create a window of potential resectability. In a late stage model of pancreas cancer in which distant metastases are present at the time of treatment, combined photodynamic therapy (PDT) and gemcitabine/abraxane led to a 10,000 fold decrease in the number of distant metastases compared to untreated controls. In comparison, gemcitabine + abraxane, the current standard of care for pancreas cancer, only led to a 100 fold cytoreduction. 50% of animals treated with PDT + gem/abraxane harbored no detectable metastases 51 days after treatment compared to 0% of gem/abraxane treated animals, suggesting that PDT plus cytoreduction could enable potentially curative surgery in a sizeable percentage of animals. The strategy presented here is rapidly translatable and holds significant promise to dramatically increase the percentage of patients that are currently eligible for curative therapy for this devastating disease. Citation Format: Sriram Anbil, Zhiming Mai, Michael Pigula, Tayyaba Hasan. Photochemistry mediated tumor priming potentiates cytoreduction of distant metastases to enable potential surgical cure in a late stage model of pancreas 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 LB-052.
Abstract 2162: KIM–1 mediatesimmune evasioninrenal cell carcinoma
Authors: Demitra M. Yotis, Bradly Shrum, Marie Sarabusky, Lakshman Gunaratnam
Journal: Cancer Research (2020)

Abstract Renal cell carcinoma (RCC) is the most common and lethal form of kidney cancer. Cancer immune evasion is a major obstacle for effective immunotherapy in RCC. Mechanisms of immune evasion are characterized by three phenotypes: Immune Inflamed; tumor contains infiltrating T cells which are rendered inactive within the tumor microenvironment due to localized inhibition. Immune Desert; tumor is devoid of activate T cells due to defective antigen presentation, and/or T cell activation. Lastly, Immune Excluded; tumor is surrounded by T cells that are unable to penetrate the parenchyma, caused by immunosuppression within the tumor stroma. Kidney Injury Molecule-1 (KIM-1) is a cell-surface glycoprotein aberrantly expressed in &amp;gt;90% of RCC tumors. The purpose of this study was to determine the pathophysiological significance of KIM-1 in RCC pathogenesis. We generated murine RCC cells (Renca) expressing KIM-1 (KIM-1pos) or control vector (KIM-1neg) using lentiviral transduction. We found that KIM-1 expression on RCC cells promoted more rapid tumor growth when injected contralaterally into syngeneic immunocompetent BALB/c mice (KIM-1neg = 263.75mm3, KIM-1pos = 849.72, p = 0.0149 &amp; KIM-1neg = 0.32g, KIM-1pos = 0.58, p = 0.0229), but not in RAG1-/- immunodeficient BALB/c mice suggesting the KIM-1 promotes tumor growth through evasion of the adapt immune system. When analyzing tumor infiltrating lymphocytes (TILs) from both tumor groups, we found a relative scarcity of CD4+ and CD8+ T cells within the KIM-1pos vs. KIM-1neg tumors. To classify the immune evasion phenotype, we analyzed localization of the immune infiltrate using immunofluorescence within KIM-1pos and KIM-1neg RCC tumors. We found significantly fewer CD3+ cells within the KIM-1pos vs. KIM-1neg tumor parenchyma (KIM-1neg = 3625.78%, KIM-1pos = 272.36%, p = 0.0410). Moreover, CD3+ cells of the KIM-1neg tumors were observed in the parenchyma, whereas CD3+ cells of the KIM-1pos tumors were localized to the tumor stroma. In addition, we observed a higher frequency of myeloid derived suppressor cells (MDSCs) within the KIM-1pos vs the KIM-1neg tumor parenchyma (KIM-1neg = 0.05, KIM-1pos = 0.19, p = 0.0266). Transcriptomic profiling of both KIM-1pos and KIM-1neg Renca cells suggests that KIM-1 promotes deposition of extracellular matrix (KIM-1neg = -1.21, KIM-1pos = 1.96-fold change), which may contribute to KIM-1-mediated immune evasion Our data suggests that KIM-1 expression in RCC promotes immune evasion by altering the tumor microenvironment resulting in an Immune Excluded phenotype. Citation Format: Demitra M. Yotis, Bradly Shrum, Marie Sarabusky, Lakshman Gunaratnam. KIM–1 mediatesimmune evasioninrenal cell carcinoma [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 2162.
Abstract 3010: VKNG 1 reverses multidrug resistance by inhibiting ABCG2 mediated drug transport in vitro and in vivo
Authors: Silpa Narayanan, Nehaben A. Gujarati, Qiuxu Teng, Jingquan Wang, Chao-Yun Cai, Yuqi Yang, Anirudh Jaganna Chintalapati, Vijaya L. Korlipara, Zhe-Sheng Chen
Journal: Cancer Research (2020)

Abstract The emergence of multidrug resistance (MDR) to chemotherapeutic drugs continues to be a major problem in the treatment of cancer. Drug resistance, either intrinsic or extrinsic is responsible for the recurrence of cancer related deaths. Understanding the drug resistant mechanisms of cancer is necessary for developing an effective treatment. ATP-binding cassette transporters are the integral transmembrane proteins which play a role in the expulsion of chemotherapeutic drugs, make the MDR more complicated. Breast cancer resistance protein (BCRP/ABCG2) is one among the MDR transporters with a wide range of substrates and overexpressed in various kinds of cancers like breast, colon, ovarian and lung cancers. An analysis of various new compounds leads to the discovery of VKNG-1 that selectively inhibits ABCG2 transporter and reverses the resistance to chemotherapeutic drugs both in vitro and in vivo. VKNG-1 selectively causes the ABCG2 inhibition and sensitizes the ABCG2 overexpressing resistant cells to the substrate anti-cancer drugs. The mechanism of action of VKNG-1 is its ability to prevent the efflux function of ABCG2 and thereby increases the intracellular accumulation of substrate drugs. In addition, there was a decrease in the expression of ABCG2 at both mRNA and protein level, but the protein translocation did not happen in the presence of VKNG-1. The induced-fit docking studies suggest the existence of strong interactions between VKNG-1and BCRP protein. In addition, VKNG-1 maintains the anti-cancer effect of irinotecan in ABCG2 overexpressing tumor xenografts and combination of VKNG-1 and irinotecan greatly inhibited the growth of S1-M1-80 resistant tumors. These results suggest that potent and selective action of VKNG-1 makes it as a promising treatment option in overcoming drug resistance in cancer. Citation Format: Silpa Narayanan, Nehaben A. Gujarati, Qiuxu Teng, Jingquan Wang, Chao-Yun Cai, Yuqi Yang, Anirudh Jaganna Chintalapati, Vijaya L. Korlipara, Zhe-Sheng Chen. VKNG 1 reverses multidrug resistance by inhibiting ABCG2 mediated drug transport 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 3010.