tbuckley/cabot-search huggingface dataset:
Abstract 2079: Ceramide nanoliposomes a novel therapeutic option for androgen receptor negative prostate cancer
Authors: Pedro Costa-Pinheiro, Abigail Heher, Michael Raymond, Kasey Jividen, Todd Fox, Mark Kester
Journal: Cancer Research (2020)

Abstract Prostate cancer (PCa) is estimated to account for 20% of newly diagnosed cancers and 10% of cancer-related deaths in US men during 2019. Prostate is a hormone-responsive gland that depends on male hormones, such as testosterone, for its normal growth and development. These hormones also play a role on the onset and progression of PCa. The androgen receptor (AR) is the main nuclear receptor activated by these hormones and regulates several key cellular pathways that contribute to worsening of the disease. Several antagonists for AR have been developed, as well as drugs that block the conversion of precursor steroids to testosterone. These drugs are extremely efficacious in patients, however within 24 months virtually all tumors recur and progress to castration resistant PCa (CRPC), a stage of disease that ultimately leads to death from PCa. To address this lack of efficacy and lack of therapeutics for CRPC, we decided to investigate the potential of ceramide nanoliposomes (CNL) as a new modality for PCa in preclinical models. Ceramide is a sphingolipid, a class of bioactive lipids that serve to keep membrane structure intact but also have the ability to trigger signaling cascades. CNL have been shown to be efficacious as a treatment in several tumor models including a successful phase 1 clinical trial in solid tumors. Strikingly, we observed that in vitro CNL is very efficacious against AR-negative PCa cells, which represent the later stages of the disease. However, in AR-positive this efficacy was reduced, but improved upon combination treatment with AR inhibitors. By combining CNL with Enzalutamide (AR antagonist) or Abiraterone acetate (testosterone synthesis inhibitor) we observed enhanced efficacy and synergistic effects. We then sought to understand the molecular mechanism underlying this synergistic effect. We observed that by blocking AR, cells were able to synthesize sphingolipids de novo and adding CNL further magnified this effect. We then looked at the expression of the key enzymes in this synthesis pathway and determined that AR negatively regulates an important subunit (SPTSSB) and this negative regulation hinders the efficacy of CNL. In conclusion, we have not only found a promising therapeutic for patients that currently have no treatment options, but also a novel molecular pathway regulated by AR in prostate cells. Citation Format: Pedro Costa-Pinheiro, Abigail Heher, Michael Raymond, Kasey Jividen, Todd Fox, Mark Kester. Ceramide nanoliposomes a novel therapeutic option for androgen receptor negative 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 2079.
Abstract 1389: Exploiting inherent DNA damage repair defects in IDH1/2 mutated gliomas with the CNS penetrant PARP inhibitor, pamiparib
Authors: Christopher Hong, Amrita Sule, Jason Beckta, Ranjini Sundaram, Ranjit Bindra
Journal: Cancer Research (2020)

Abstract Our group recently demonstrated that IDH1/2 mutated gliomas exhibit intrinsic homologous recombination (HR) defects mediated by the oncometabolite, 2HG. These defects render IDH1/2 mutated cells exquisitely sensitive to PARP inhibitors (PARPi's), which suggests a novel therapeutic strategy. Here, we studied the potential in vitro and in vivo efficacy of a CNS penetrant PARPi, pamiparib, in combination with radiation therapy (RT) and temozolomide (TMZ) against IDH1/2 mutated gliomas. Our central hypothesis is that multi-modality therapy using agents that are active against 2HG producing cells will increase efficacy, while allowing lower doses of RT and TMZ as a means to mitigate normal tissue toxicity. We performed a comprehensive series of DNA repair functional studies, short and long term viability assays, as well as in vivo studies, using engineered and patient-derived IDH1/2 mutant glioma models. We tested unique combinations of pamiparib, TMZ and RT in these experiments. In vitro short term viability assays and long-term clonogenic survival assays in model IDH1 wild-type (WT) and R132H mutated glioma cells demonstrated that the mutation confers enhanced TMZ sensitivity (IC50 602 vs. 9.5 uM, respectively). A similar differential sensitivity was observed with RT. We also demonstrated significant, mutant IDH1 selective pamiparib sensitivity in vitro (IC50 0.67 vs. 141 uM). Western blot analysis of PARylation, a functional readout of PARPi activity, confirmed PARylation inhibition by pamiparib in a dose dependent manner. Subsequently, we demonstrated synergistic interactions between TMZ and RT combined with pamiparib, particularly at low doses of both DNA damaging agents, in an IDH1 selective manner. Finally, we demonstrated the activity of PARPi's against IDH1 mutant tumors in vivo, including pharmacodynamic and pharmacokinetic properties of pamiparib on target activity within the brain. Pamiparib is a promising, CNS penetrant PARP inhibitor that may selectively target IDH1/2 mutated gliomas, based on intrinsic HR defects associated with these tumors. Pamiparib appears to act synergistically with TMZ and RT, which are the backbone of GBM therapies. These data lay the groundwork for a future trial testing “trimodality therapy” (i.e., pamiparib, RT and TMZ) against IDH1/2 mutant gliomas. Citation Format: Christopher Hong, Amrita Sule, Jason Beckta, Ranjini Sundaram, Ranjit Bindra. Exploiting inherent DNA damage repair defects in IDH1/2 mutated gliomas with the CNS penetrant PARP inhibitor, pamiparib [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 1389.
Abstract 2075: GPCRs for pituitary adenylate cyclase activating polypeptide regulate transactivation of HER3 in non-small cell lung cancer cells
Authors: Terry W. Moody, Lingaku Lee, Robert T. Jensen
Journal: Cancer Research (2020)

Abstract HER3, which lacks intrinsic kinase activity, plays an important role in cancer proliferation by formation of heterodimers with the EGFR or HER2 (Kiavue et al., Oncogene, 2019). Peptide GPCRs for pituitary adenylate cyclase activating polypeptide (PACAP) stimulate growth by transactivation of the EGFR and HER2 (Moody et al., JPET, 2012 and Peptides, 2019), but its effect on HER3 is unknown. The ability of PACAP to cause tyrosine phosphorylation of the EGFR, HER2 and HER3 was investigated. Using a panel of 17 non-small cell lung cancer (NSCLC) cell lines, mRNA for EGFR, HER2, HER3 was detected in 94%, 88%, and 100% of the cell lines, respectively. Addition of 100 nM PACAP but not vasoactive intestinal peptide to A549 cells increased EGFR, HER2 and HER3 tyrosine phosphorylation by 420, 240 and 190%, respectively. The increase is EGFR tyrosine phosphorylation was blocked by gefitinib or PACAP(6-38), a PAC1 antagonist. The increase in HER2 tyrosine phosphorylation caused by PACAP was inhibited by Herceptin or PACAP(6-38). The increase in HER3 tyrosine phosphorylation caused by PACAP was inhibited by the HER3 blocking antibody mAb3481 or PACAP(6-38). Immunoprecipitation experiments indicated the PACAP addition to A549 cells resulted in the formation of EGFR/HER2 and HER2/HER3 heterodimers, whereas addition of EGF resulted in EGFR/HER2 heterodimers and addition of the HER3 agonist neuregulin-1 resulted in HER2/HER3 heterodimers. Addition of N-acetyl-cysteine (antioxidant), Tiron (superoxide scavenger) or diphenylene iodonium (Nox/Duox inhibitor) impaired the ability of PACAP to cause EGFR, HER2 or HER3 transactivation. The results indicate that reactive oxygen species are essential for PACAP to cause EGFR, HER2 or HER3 transactivation in non small cell lung cancer cells. Citation Format: Terry W. Moody, Lingaku Lee, Robert T. Jensen. GPCRs for pituitary adenylate cyclase activating polypeptide regulate transactivation of HER3 in non-small cell lung cancer 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 2075.
Abstract 367: The role of A20 - Cdc20 axis promotes tumorigenesis and metastasis in triple negative breast cancer
Authors: Chaeun Song
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) has a higher mitotic index compared to other types of breast cancer yet Ki-67 values are still being used, despite an unclear mechanism. Here we found that the gene Cell-Division Cycle 20 (CDC20), an essential mitotic factor, was highly expressed in TNBC cell lines by using a NCBI GEO database. CDC20 was also negatively correlated with TNBC metastasis and recurrence. CDC20 deficiency results in the decreasing of TNBC cancer cell growth and migration, and mitosis inhibitors blocked TNBC cancer cells growth and metastasis. Interestingly, CDC20 stability is regulated by tumor necrosis factor, alpha-induced protein 3 (TNFAIP3 /A20). CDC20 expression show positive correlation with A20 in TNBC patient samples but not HR positive or HER2 breast cancer patients. A20 deficiency also inhibits cell migration and invasion through the decreasing of CDC20 protein level. Our findings uncover a critical role of the A20-CDC20 axis in tumor growth and metastasis of TNBC and suggest A20 or CDC20 is a novel therapeutic target in TNBC. Citation Format: Chaeun Song. The role of A20 - Cdc20 axis promotes tumorigenesis and metastasis in triple negative 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 367.
Abstract 60: Semaphorin 7a promotes cell survival and resistance to endocrine therapy in ER+ breast cancer
Authors: Traci Renae Lyons
Journal: Cancer Research (2020)

Abstract Estrogen receptor positive (ER+) breast cancers comprise the largest percentage, ~70%, of all breast cancers diagnosed in the Unites States. Despite the development of effective anti-estrogen based therapies, such as tamoxifen, aromatase inhibitors, and fulvestrant, 1 in 5 women with an ER+ tumor will experience recurrence within 10 years of diagnosis. Thus, the largest number of breast cancer-related deaths each year are attributed to ER+ breast cancers. Additionally, metastatic ER+ breast tumors uniformly develop resistance to anti-estrogen-based therapies, including combination targeted therapies with CDK4/6 and mTOR inhibitors, which represent some of the best therapeutic advances of the last five years and reflect our increasing understanding of cross-targeting to overcome acquired resistance. Our studies have shown that Semaphorin 7a expressing tumors are resistant to ER targeting therapies, including tamoxifen and fulvestrant. Furthermore, Semaphorin 7a expressing tumors do not respond to CDK4/6 inhibition. We have utilized luciferase reporter assays to show that Semaphorin 7a is initially regulated by ER; we then utilized overexpression studies to show that sustained upregulation of Semaphorin 7a results in downregulation of ER in xenograft models. This downregulation of ER is accompanied by upregulation of cell survival signaling mediated by pro-survival kinase Akt. In TCGA and METABRIC datasets, Semaphorin 7a expression is associated with significant decreases in overall survival. Furthermore, using KmPlot analysis, we have shown that Semaphorin 7a expression in patients treated with endocrine therapy predicts for poor survival rates. Thus, we sought to determine whether Semaphorin 7a expressing tumors would be susceptible to PI3K/Akt targeted therapies. We observe that Semaphorin 7a expressing tumors are sensitive to PI3K/Akt inhibition, as well as to inhibition of the ER target gene Bcl2. Thus, we suggest that patients with high Semaphorin 7a expression be considered as candidates for the addition of Venetoclax, an FDA approved Bcl2 targeted therapy, to their current therapeutic regimen. As Venetoclax is in Phase II trials in combination with fulvestrant for advanced CDK4/6 inhibitor refractory breast cancer, we believe our results could be rapidly translated to the clinical setting and will improve outcomes for the thousands of ER+ breast cancer patient that develop resistance to endocrine therapy. Citation Format: Traci Renae Lyons. Semaphorin 7a promotes cell survival and resistance to endocrine therapy in ER+ 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 60.
Targeted galectin-7 inhibition with ultrasound microbubble targeted gene therapy as a sole therapy to prevent acute rejection following heart transplantation in a Rodent model
Authors: Zhuo Wang, Shuangquan Jiang, Shouqiang Li, Weidong Yu, Jianfeng Chen, Dandan Yu, Chen Zhao, Yingjie Li, Kai Kang, Ranran Wang, Mengmeng Liang, Mingyuan Xu, Yanmei Ou, Piyu Li, Xiaoping Leng, Jiawei Tian, Thomas R-Porter
Journal: Biomaterials (2020)

Despite significant advances in transplantation, acute cellular rejection (AR) remains a major obstacle that is most prevalent in the first months post heart transplantation (HT). Current treatments require high doses of immunosuppressive drugs followed by maintenance therapies that have systemic side effects including early infection. In this study, we attempted to prevent AR with a myocardial-targeted galectin-7-siRNA delivery method using cationic microbubbles (CMBs) combined with ultrasound targeted microbubble destruction (UTMD) to create local immunosuppression in a rat abdominal heterotopic heart transplantation acute rejection model.Galectin-7-siRNA (siGal-7) bound to CMBs were synthesized and effective ultrasound-targeted delivery of siGal-7 into target cells confirmed in vitro. Based on these observations, three transplant rat models were tested：①isograft (ISO); ② Allograft (ALLO) +UTMD; and ③ALLO + PBS. UTMD treatments were administered at 1, 3, 5, 7 days after HT. Galectin 7 expression was reduced by 50% compared to ALLO + PBS (p < 0.005), and this was associated with significant reductions in both galectin 7 and Interleukin-2 protein levels (p < 0.001). The ALLO + UTMD group had Grade II or less inflammatory infiltration and myocyte damage in 11/12 rats using International Society For Heart and Lung Transplantation grading, compared to 0/12 rats with this grading in the ALLO + PBS group at 10 days post HT (p < 0.001).Ultrasound-targeted galectin-7-siRNA knockdown with UTMD can prevent acute cellular rejection in the early period after allograft heart transplantation without the need for systemic immunosuppression.Microbubble, Acute Rejection, Heart Transplantation, Galectin-7, RNA.
Abstract 3106: Accurate estimation of circulating tumor DNA fraction from ultra low-pass whole-genome sequencing
Authors: Justin Finkle, Christine Lo, Hala Boulos, Terri Driessen, Wei Zhu, Robert Tell
Journal: Cancer Research (2020)

Abstract Early detection of recurrence is critical to improve the survival of cancer patients. Blood-based “liquid biopsies” provide a minimally invasive method to detect variants, and ultra low-pass whole-genome sequencing (LPWGS) can accurately and sensitively detect low fractions of circulating tumor DNA in blood plasma. We previously conducted LPWGS on approximately 400 samples (primarily from lung, breast, prostate, and pancreatic cancers) residual to samples previously analyzed with our xF liquid biopsy assay. In this analysis, we demonstrate that circulating tumor fraction estimates from LPWGS correlate with the maximum detectable pathogenic variant allele fraction, and where there are discrepancies the LPWGS estimates are more reasonable. We also show differences in tumor fractions and ploidy between cancer cohorts and stages. Our results suggest LPWGS provides an accurate measure of the fraction of circulating DNA derived from tumors across cancer cohorts and stages. Citation Format: Justin Finkle, Christine Lo, Hala Boulos, Terri Driessen, Wei Zhu, Robert Tell. Accurate estimation of circulating tumor DNA fraction from ultra low-pass whole-genome sequencing [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 3106.
Abstract 1768: Identification of a potent, orally-available SMARCA2/4 inhibitor with in vitro and in vivo activity in preclinical models of SMARCA4-mutant NSCLC
Authors: Allison E. Drew, Suzanne L. Jacques, Lindsey W. Eichinger, Chloe Pantano, Vinny Motwani, Cuyue Tang, Cuyue Tang, Neil Farrow, Dorothy Brach, Selene Howe, Alejandra Raimondi, Daniel T. Dransfield, Kenneth W. Duncan, Kim Stickland, Liyue Huang, John Lampe
Journal: Cancer Research (2020)

Abstract SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily A member 2 (SMARCA2) is an ATP-dependent DNA helicase and a catalytic component of the SWI/SNF complex. SWI/SNF-mediated nucleosome remodeling is a critical regulator of chromatin accessibility resulting in transcriptional regulation of gene sets that determine and maintain cell state. The role of SMARCA2 as the catalytic driver of SWI/SNF activity is mutually exclusive with that of its close paralog, SMARCA4. Loss of functional SMARCA4, as is reported in a subset of NSCLC and other cancer types generally confers a dependency on SMARCA2. Cancers lacking functional SMARCA4 have been shown to be sensitive to loss of SMARCA2 function either through genetic ablation or the use of a small molecule SMARCA2/4 inhibitor. We describe the identification and characterization of a small molecule SMARCA2/4 inhibitor Compound 1 and its selective activity in the SMARCA4-mutant setting both in in vitro and in vivo model systems. The compound demonstrates inhibition of SMARCA2 and SMARCA4 enzymatic activity in biochemical assays and broad selectivity against other helicases. Selective sensitivity in anti-proliferative assays of 15-fold was observed in NSCLC cell lines with SMARCA4 protein loss compared to those harboring WT SMARCA4 protein. Oral dosing demonstrates dose-dependent in vivo SMARCA2 inhibition and anti-tumor activity in SMARCA4-mutant NSCLC xenograft models. This compound is suitable for further exploration of the role of SMARCA2/4 and SWI/SNF in vitro and in vivo in cancer and other indications. Citation Format: Allison E. Drew, Suzanne L. Jacques, Lindsey W. Eichinger, Chloe Pantano, Vinny Motwani, Cuyue Tang, Cuyue Tang, Neil Farrow, Dorothy Brach, Selene Howe, Alejandra Raimondi, Daniel T. Dransfield, Kenneth W. Duncan, Kim Stickland, Liyue Huang, John Lampe. Identification of a potent, orally-available SMARCA2/4 inhibitor with in vitro and in vivo activity in preclinical models of SMARCA4-mutant NSCLC [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 1768.
Abstract 3196: Analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRLX301, a nanoparticle of docetaxel
Authors: Eiman Mukhtar, Daniel Worroll, Giuseppe Galletti, Shelly Schuster, Sarina A. Piha-Paul, Paraskevi Giannakakou
Journal: Cancer Research (2020)

Abstract We reviewed the radiographic response of three patients with metastatic castration-resistant prostate cancer (mCRPC) treated with CRLX301, a docetaxel nanoparticle. For these three patients, we isolated and analyzed circulating tumor cells (CTC) to explore microtubule (MT) drug-target engagement (MT-DTE) as a biomarker of response to treatment. We quantitatively assessed the MT cytoskeleton in CTCs from pre- and post-treatment patient samples as a potential read-out of CRLX301 activity. We isolated CTCs using negative CD45+ depletion and subjected them to multiplex confocal microscopy using our established protocol. CTCs were identified as CD45-/CK+/DAPI+ cells and MT-DTE was determined using our developed, semi-high-throughput, high-content imaging algorithm to quantify MT bundling in CTCs across multiple time points, from baseline to on-treatment to disease progression. We collected CTCs at seven time points from three mCRPC patients. Clinical response was evaluated by RECIST v.1.1 criteria in those patients with measurable disease. Of the three patients who received CRLX301, one experienced partial response and two patients were unevaluable per RECIST given bone only disease, however showed stable disease clinically per bone scans. MT-DTE across all time points revealed that, early time points within four and 24 hours of drug administration exhibited the highest levels of drug engagement as compared to baseline but did not discriminate the responding patient from the patients with stable disease. However, the limited sample size makes this an observation that warrants validation in a larger cohort of patients. We observed that the CTCs collected one week after the first or second dose of CRLX301 treatment in the responding patient had numerically higher levels of MT-DTE as compared to the other two patients. MT-DTE can be detected and analyzed quantitatively in CTCs by tubulin immunofluorescence. The clinical utility of the 1-week CTC DTE should be tested and validated in future clinical trials involving nanoparticle formulations of taxanes or taxanes in general. Citation Format: Eiman Mukhtar, Daniel Worroll, Giuseppe Galletti, Shelly Schuster, Sarina A. Piha-Paul, Paraskevi Giannakakou. Analysis of taxane drug target engagement of microtubules in circulating tumor cells from metastatic castration resistant prostate cancer patients treated with CRLX301, a nanoparticle of docetaxel [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 3196.