bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3969: Y842 mutations in the activation loop of FLT3 regulates drug response in FLT3-ITD positive acute myeloid leukemia
Authors: Al Ashiri Lina , Moharram Sausan , Purohit Rituraj , Uddin Julhash Kazi , Rönnstrand Lars 
Published: June 2022

Abstract
Acute myeloid leukemia (AML) is an aggressive form of blood cancer with a poor prognosis. Approximately 30% of AML patients carry mutations in the type III receptor tyrosine kinase FLT3. The most common form of FLT3 mutations includes internal tandem duplication (ITD) mutations, which are also associated with poor clinical outcomes. Several inhibitors of FLT3 have been developed and are under clinical trials. Major problems in targeting FLT3-ITD include acquired resistance to the inhibitors which is mediated by secondary point mutations in FLT3. The activity of many, but not all, tyrosine kinases is dependent on the well-conserved tyrosine residue in the activation loop for receptor activation. For instance, we have recently shown that the KIT receptor is dependent on its activation loop tyrosine for downstream signaling and receptor stability, but not for the activation of the receptor. In many AML patients, FLT3-ITD mutations in combination with mutations in the activation loop tyrosine residue (Y842) result in drug resistance. We therefore stably transduced cells with FLT3-ITD in combination with different Y842 mutants (Y842C and Y842F). Using MM-PBSA, we found that the introduction of the Y842C and Y842F point mutations changed the binding energy of the FLT3 inhibitors quizartinib, sorafenib, and midostaurin in silico. In addition, the mutants displayed a change in drug response and apoptosis levels after treatments with FLT3 inhibitors in vitro. Previous data from our lab also shows that the Y842F mutant resulted in delayed tumor formation in vivo, indicating that the phosphorylation of the activation loop tyrosine is an important event in FLT3-ITD-mediated transformation. All in all, our data suggest that the activation loop tyrosine residue in FLT3-ITD positive cells plays an important role in drug response and tumor formation.
Citation Format: Lina Al Ashiri, Sausan Moharram, Rituraj Purohit, Julhash Kazi Uddin, Lars Rönnstrand. Y842 mutations in the activation loop of FLT3 regulates drug response in FLT3-ITD positive acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3969.
Abstract 3987: Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death
Authors: Barnett Katherine , Kwon Hyuk Jean , Novak Orlandi , Eberhart Charles , Raabe Eric 
Published: June 2022

Abstract
Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. We have previously shown that the brain penetrant class 1 HDAC inhibitor RG2833 (RGFP109) inhibits cell growth (MTS assay for HSJD007 p=0.0004, JHH-DIPG1 p=0.001, SF-7761 p=0.04, SU-DIPG13 p=0.01 by t-test), reduces proliferation (phospho-Rb Western blot, BrdU immunofluorescence HSJD007 p=0.008, JHH-DIPG1 p=0.0002 by t-test), and induces apoptosis (cPARP Western blot, cleaved caspase 3 immunofluorescence HSJD007 p&lt;0.003, JHH-DIPG1 p=0.0026 by t-test) in multiple DIPG cell lines. We have also shown that treatment of a DIPG flank tumor mouse model with RG2833 alone for 1 week suppresses flank tumor growth (p&lt; 0.005 by t-test) and induces apoptosis (Western blot for cPARP). In a DIPG orthotopic mouse model, we confirmed that RG2833 100mg/kg has on target activity in the mouse brain (Western blot for histone 3 acetylation) without causing toxicity. We next sought to identify a rational combination therapy to enhance RG2833 efficacy against DIPG. We found that RG2833 increases expression of negative cell cycle regulators p16, p21, and p27 and decreases expression of anti-apoptotic proteins BCL-2, BCL-XL, and XIAP (assessed by Western blot). Given that PI3K/mTOR pathway is upregulated in DIPG and plays an important role in cell cycle regulation via p21 and the FOXO signaling, we hypothesized that RG2833 would synergize with inhibitors of PI3K/mTOR. The brain penetrant PI3K/mTOR inhibitor Paxalisib is currently being evaluated in a phase 1 clinical trial of children with DIPG. We found that RG2833 has strong synergism with Paxalisib at clinically achievable doses (Loewe synergy scores by SynergyFinder for SF7761 and JHH-DIPG1 &gt;20). Evaluation of combination treatment for apoptotic effects in vitro and in vivo are ongoing. These findings identify RG2833 and Paxalisib as a promising combination therapy for DIPG.
Citation Format: Katherine Barnett, Hyuk Jean Kwon, Orlandi Novak, Charles Eberhart, Eric Raabe. Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3987.
Abstract 4022: ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models
Authors: Knoerzer Deborah , Reddy Anupama , Derti Adnan , Emery Caroline M. 
Published: June 2022

Abstract
Atypical BRAF (non-V600) alterations comprise approximately half of all BRAF mutations in cancer and can be categorized according to characteristics of molecular signaling (either Class II or III). Atypical BRAF alterations are rare (approximately 3% across all human cancers) and there are currently no approved therapies for this indication. As next-generation sequencing becomes standard clinical practice, oncologists are frequently identifying atypical BRAF alterations in their patients’ tumors. The efficacy of the first-in-class ERK1/2 inhibitor, ulixertinib (BVD-523), was assessed across 10 patient-derived xenograft (PDX) models, which harbored class II or III BRAF alterations (5 models with type II alterations, 4 models with class III, and 1 model with both class II and III). Responses ranging from robust regression to moderate tumor growth delay were observed in 9/10 models. RNA sequencing was performed on tumors from the vehicle-treated and ulixertinib-treated groups with three replicates per PDX model. The samples were collected 2 hours after the last dose of treatment. Expression of the mutant BRAF alleles was readily confirmed from RNA-seq data in all PDX models. In addition, gene expression analysis showed differential expression of MAPK pathway genes in responders compared to the non-responders.
In summary, ulixertinib has exhibited strong pre-clinical activity in a variety of patient-derived xenograft models with atypical BRAF alterations. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, harboring specific BRAF mutations (G469A, L485W, or L597Q) and is currently under clinical evaluation in patients with tumors harboring any atypical BRAF alteration (NCT04488003).
Citation Format: Deborah Knoerzer, Anupama Reddy, Adnan Derti, Caroline M. Emery. ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4022.
Abstract 4035: Driver-gene dependencies reveal clinically actionable drug repositioning opportunities
Authors: Babak Tomas , Vermeulen Michael , Villa Doris Coto , Craig Andrew 
Published: June 2022

Abstract
Cancer cell lines have numerous characteristics that make them favorable pre-clinical research models, yet they are notoriously poor at predicting drug response in the clinic. Here we sought to investigate the utility of synthetic lethality (SL) interactions discovered from large-scale CRISPR functional screens (i.e. the BROAD and Sanger Cancer Dependency Maps or "DepMap") as predictors of targets that validate in patients. Mutual exclusivity, the phenomenon where two genes are rarely mutated together in the same tumor, is a powerful clinical-stage readout that can be caused by synthetic lethality. We found that SL interactions discovered in DepMap are significantly more likely to be mutually exclusive in TCGA when they include a driver (tumor-suppressor/oncogene). These SL interactions represent high-value targeting opportunities with the advantage of clear patient selection criteria based on their driver mutation status. In an effort to identify drugs that target these proteins as potential repurposing opportunities, we found that pharmacogenomic inhibition rarely invokes the same target dependencies as a genetic deletion of the drug target. Nonetheless, we identified several dozen "clean" drugs with potential for repositioning and validated the top candidates in PDx. Although tumours are more heterogenous than cancer cell lines, we show that cell line viability readouts linked to single-gene/drug perturbations can yield accurate predictions of clinical efficacy when tied to tumor-driver biology.
Citation Format: Tomas Babak, Michael Vermeulen, Doris Coto Villa, Andrew Craig. Driver-gene dependencies reveal clinically actionable drug repositioning opportunities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4035.
Abstract 4038: Study of therapeutic effects of polyisoprenylated cysteinyl amide inhibitors on lung cancer cells of black patients using 3D-Printed alveolar model
Authors: Belony Nadine , Ren Bing , Pham Phuc , Gregory Matthew , Puente Pablo E. , Lamango Nazarius S. , Offringa Ite A. , Huang Yong 
Published: June 2022

Abstract
Lung cancer is one of the top five deadliest cancers, and black Americans have a higher mortality rate when compared to white Americans even though they smoke relatively fewer cigarettes. Lung adenocarcinoma (LUAD) is the most common histological lung cancer subtype in all population groups including blacks. There are no in vitro model systems to study lung cancer in black subjects, and there is only one lung adenocarcinoma cell line from a black patient (NCI-H23). Here we aim to address the lack of in vitro models to study black LUAD. Using three-dimensional (3D) biofabrication technologies, we’ve developed a thick vascularized tissue model to recapitulate physiologically relevant heterogeneous human alveoli. Specifically, the blood-air barrier of the alveolar model is simulated with two perfusable channels embedded in a thick vascularized tissue construct: a helical blood channel and a straight air channel. Spatially, the air channel is in the center and is surrounded by the blood channel. Human endothelial cells are seeded onto the inner surface of the blood channel and NCI-H23 cells (which carry a KRAS mutation) or untransformed alveolar epithelial cells derived from black subjects, are seeded on the inner surface of the air channel. The blood and air channels are perfused using cell medium and oxygenated air, respectively. The model is used for the study of potential LUAD therapeutic agents such as polyisoprenylated cysteinyl amide inhibitors (PCAIs), which target and disrupt the RAS-mediated signaling pathway. KRAS is the most commonly mutated oncogene in LUAD in blacks, and our experiments are aimed at ensuring that PCAIs are effective in black LUAD and may offer better treatment outcomes for ethnically/racially diverse patients in whom the RAS signaling pathway is frequently altered and for whom pharmaceutical therapy is necessitated by the late diagnoses.
Citation Format: Nadine Belony, Bing Ren, Phuc Pham, Matthew Gregory, Pablo E. Puente, Nazarius S. Lamango, Ite A. Offringa, Yong Huang. Study of therapeutic effects of polyisoprenylated cysteinyl amide inhibitors on lung cancer cells of black patients using 3D-Printed alveolar model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4038.
Abstract 4042: Genomic and pharmaco-genomic profiling of pancreatic cancer using patient-derived organoids
Authors: Deschênes Astrid , Belleau Pascal , Plenker Dennis , Habowski Amber , Patel Hardik , Park Youngkyu , Tiriac Hervé , Baker Lindsey A. , Krasnitz Alexander , Tuveson David A. 
Published: June 2022

Abstract
Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal common malignancies, with little improvement in patient outcomes over the past decades. We have developed a novel methodology to culture organoids from both human healthy pancreatic ductal epithelial tissues and PDAC. A collection of patient-derived organoids (PDO), grown using this protocol, numbers over 100 models to date. The 100% neoplastic purity of the organoid cultures facilitates molecular characterization that has been traditionally challenging in the pauci-cellular state of primary pancreatic tumors. These PDO open new opportunities for deep genomic and transcriptomic studies of the disease, and for individualized drug screens. Here we demonstrate that accurate predictive models of response to pharmacological treatments of PDAC can be developed using data from such screens alongside molecular profiles of the PDO.
Methods: Molecular analysis of the PDO library yielded genomic and transcriptional profiles of the cultures, including those of copy number variation (CNV), mutations in the exome and mRNA expression. From these, we drew features for prediction of drug responses. Using molecular features drawn from these profiles, we developed a panel of predictive models for response to standard-of-care cytotoxic agents and a number of targeted treatments. We employed Random Forest (RF) regression as a machine-learning tool for this purpose.
Results: PDO are faithful models of PDAC, whose molecular features closely resemble those of PDAC tumor specimens. Using a subset of these features, we were able to accurately learn PDO responses to cytotoxic agents: for each of the five agents considered, the predicted drug response correlated strongly (p &lt; 10-7) with the observed value. A similar accuracy of prediction was achieved for a number of targeted agents.
Conclusion: PDOs are a valuable resource for molecular and pharmacological characterization of PDAC, with a potential to guide clinical decisions with regard to treatment.
Citation Format: Astrid Deschênes, Pascal Belleau, Dennis Plenker, Amber Habowski, Hardik Patel, Youngkyu Park, Hervé Tiriac, Lindsey A. Baker, Alexander Krasnitz, David A. Tuveson. Genomic and pharmaco-genomic profiling of pancreatic cancer using patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4042.
Abstract 405: A new mechanism of drug resistance in cancer: extracellular ATP-induced resistance by macropinocytosis-mediated internalization and redox changes
Authors: Zhang Haiyun , Chen Xiaozhuo 
Published: June 2022

Abstract
Drug resistance are responsible for most relapses and up to 90% of cancer related death. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism. In tumor microenvironment, intratumoral extracellular ATP (eATP) levels are 1,000 times or more higher than those in corresponding normal tissues. Our previous studies have shown that eATP can be taken up by cancer cell via macropinocytosis, leading to substantial increase in intracellular ATP levels. We found that this high intracellular ATP levels contribute to drug resistance in several ways: first, it directly fueled and enhanced drug-pumping activity of major ATP-binding cassette (ABC) multidrug transporters, which are located in plasma membrane and can pump out a wide range of substrates including anticancer drugs, leading to reduced intracellular drug retention. Secondly, ATP treatment upregulated gene expression of the major ABC transporters, and this gene regulatory effect of ATP was comparable to TGF-beta, which is a well-established epithelial-mesenchymal transition (EMT) inducer, and EMT is known to induce ABC transporter expression and drug resistance. Moreover, eATP treatment led to an increase in intracellular glutathione (GSH) levels, probably by enhancing GSH synthesis. Increased GSH levels have been described to significantly contribute to drug resistance. We also found eATP altered cellular redox state, which potentially stimulates EMT. Furthermore, we performed RNA-sequencing and identified several genes that may serve as downstream factors of eATP in promoting EMT and drug resistance. We are currently investigating the roles of these genes by knocking down gene expression or knocking out these genes.
Citation Format: Haiyun Zhang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: extracellular ATP-induced resistance by macropinocytosis-mediated internalization and redox changes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 405.
Abstract 4068: The potent quadruplex-binding compound SOP1812 shows potent anti-proliferative activity in a prostate cancer cell panel and anti-tumor activity in an in vivo model of metastatic prostate cancer
Authors: Williams Nicole , Worthington Jenny , Neidle Stephen , Ahmed Ahmed 
Published: June 2022

Abstract
The compound SOP1812, a tetra-substituted naphthalene diimide (ND) derivative has been designed as a potent compound for targeting quadruplex sequences in cancer genes. It has been previously disclosed to have single-digit nM anti-proliferative activity in a panel of human cancer cell lines (Ahmed et al., ACS Med Chem Lett, 2020, 11, 1634-1644). It also has significant anti-tumor activity in several models for pancreatic cancer. We have also previously shown that two early-generation ND derivatives are active in both androgen-positive and negative prostate cancer cell lines (Mitchell et al, Biochemistry, 2013, 32, 1429-1436) and that these compounds down-regulate the transcription of quadruplex-containing genes such as c-MYC. We now report that this compound also shows significant anti-proliferative activity in several prostate cancer cell lines, notably with a GI50 value of 3 nM in the PC3 cell line. Abiraterone has a GI50 in this line of 4820 nM. By contrast SOP1812 has a GI50 of 247 nM in the LNCaP line, which is also derived from a patient with metastatic prostate cancer but is androgen positive. The PC3 line is derived from a metastatic carcinoma following androgen suppression therapy and is thus androgen independent and is a model for castration-resistant prostate cancer when hormone therapies are no longer effective. We have evaluated the activity of SOP1812 in the PC3 xenograft model using a twice-weekly 1 mg/kg dose regimen IV administered, against a saline control and abiraterone, at a daily dose of 200 mg/kg, administered by the PO route, both over a 28-day period. No weight loss was observed in treated animals with either drug. SOP1812 produced statistically significant tumor shrinkage (P value of 0.0008) relative to the controls, with a T/C value of 33.5% on day 28. Abiraterone treatment resulted in a T/C value of 61.6%, with a P value of 0.0382. SOP1812 is bio-available at therapeutic doses and is well tolerated at these levels in this animal model. It is currently being evaluated as a candidate for clinical development by Qualigen Therapeutics Inc.
Citation Format: Nicole Williams, Jenny Worthington, Stephen Neidle, Ahmed Ahmed. The potent quadruplex-binding compound SOP1812 shows potent anti-proliferative activity in a prostate cancer cell panel and anti-tumor activity in an in vivo model of metastatic prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4068.
Abstract 4071: Utilizing colforsin as a novel therapeutic for high grade serous ovarian cancer treatment
Authors: Knarr Matthew , Reavis Hunter , Mitchell Marilyn , Drapkin Ronny 
Published: June 2022

Abstract
Epithelial ovarian cancer (EOC) is currently the deadliest gynecological cancer with approximately 20,000 new cases and 15,000 deaths per year in the United States. Ovarian cancer can be stratified into distinct subtypes of which high-grade serous ovarian cancer (HGSOC) comprises 90% of all cases. The majority of HGSOC patients are diagnosed with late-stage disease and have a poor prognosis with a 5-year survival rate of less than 30%. Thus, there is a critical need to develop novel therapeutic strategies to improve patient treatment and survival outcomes. Our lab has recently discovered that the small molecule colforsin has potent anti-cancer properties when used to treat HGSOC in vitro and in vivo. Colforsin is a water-soluble derivative of forskolin, and acts as an activator of cAMP signaling via direct binding and activation of adenylyl cyclase. It is currently in clinical use for treatment of conditions such as glaucoma, diabetes, and liver fibrosis. This makes colforsin a prime candidate for drug repurposing to treat ovarian cancer. Our data show that colforsin can induce cell cycle arrest and cell death in established HGSOC cell line models in vitro. We have also found that colforsin can inhibit tumor growth and tumor burden in an intraperitoneal model of HGSOC using HEYA8 cells. In addition, we have also found that colforsin acts synergistically with cisplatin to cause HGSOC cell death. Taken together, our data show that colforsin has potential as a new therapeutic tool to aid in HGSOC treatment in combination with existing therapies.
Citation Format: Matthew Knarr, Hunter Reavis, Marilyn Mitchell, Ronny Drapkin. Utilizing colforsin as a novel therapeutic for high grade serous ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4071.