bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 2585: Targeted protein upregulation strategy potentiates STING agonist immunotherapy
Authors: Cho Wansang , Won Solchan , Choi Yoona , Park Jong Beom , Park Jun-Gyu , Yi Sihyeong , Kim Caroline E. , Narayana Chintam , Lee Dong-Sup , Park Seung Bum 
Published: June 2022

Abstract
As cancer immunotherapy has been emerged as a new pillar of cancer therapy, many strategies modulating host immunity were suggested for cancer treatment. Stimulator of interferon genes (STING) is a promising target for anticancer immunotherapy. However, dysregulated STING expression, or poor pharmacokinetic profiles of STING agonists pose major challenges. Recently, modulating target protein levels via the ubiquitin-proteasome system, such as proteolysis-targeting chimera (PROTAC), has broadened the scope of pharmacological inventions. Herein, we propose UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to overcome these limitations. We discovered the small molecule SB24011 that inhibits STING-E3 ligase interaction, thereby induces the blockade of E3 ligase-mediated STING degradation. As a result, SB24011 enhanced the STING agonist-mediated immune responses by upregulating cellular STING protein level. Thus, co-administration of SB24011 markedly improved the immuno-oncological efficacy of STING agonist cGAMP and anti-PD-1 therapy for tumor regression and robust systemic antitumor response. Taken together, we successfully demonstrated that targeted STING protein upregulation is a promising strategy for cancer immunotherapy.
Citation Format: Wansang Cho, Solchan Won, Yoona Choi, Jong Beom Park, Jun-Gyu Park, Sihyeong Yi, Caroline E. Kim, Chintam Narayana, Dong-Sup Lee, Seung Bum Park. Targeted protein upregulation strategy potentiates STING agonist immunotherapy [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 2585.
Abstract 2611: The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal cancer
Authors: Invrea Federica , Carugo Alessandro , Arena Sabrina , Bardelli Alberto , Draetta Giulio F. , Medico Enzo 
Published: June 2022

Abstract
Colorectal cancer (CRC) is a heterogeneous disease with a wide spectrum of clinical outcomes, from indolent resectable disease to aggressive-metastatic cases. Primary and acquired resistance limits the efficacy of available treatments, and the identification of effective drug combinations is needed to further improve patients' outcomes. We previously found that the NEDD8-activating enzyme inhibitor pevonedistat induced tumor stabilization in preclinical models of poorly differentiated, clinically aggressive CRC resistant to available therapies. To identify drugs that can be effectively combined with pevonedistat, we performed a "drop-out" loss-of-function synthetic lethality screening with an shRNA library covering 200 drug-target genes in four different CRC cell lines. Multiple screening hits were found to be involved in the EGFR signaling pathway, suggesting that, rather than inhibition of a specific gene, interference with the EGFR pathway at any level could be effectively leveraged for combination therapies based on pevonedistat. Exploiting both BRAF-mutant and RAS/RAF wild-type CRC models, we validated the therapeutic relevance of our findings by showing that combined blockade of NEDD8 and EGFR pathways led to increased growth arrest and apoptosis both in vitro and in vivo. Pathway modulation analysis showed that compensatory feedback loops induced by single treatments were blunted by the combinations. Our results suggested possible therapeutic opportunities in specific CRC clinical settings. We further focused on HER2 amplified CRC cells and we observed cooperation between pevonedistat and HER2/EGFR blockade by the trastuzumab + lapatinib combination -the current standard treatment for HER2-amplified CRC. In addition, to confirm cooperation in reducing colony formation in vitro, we explored the effect of pevonedistat on long-term persisters, i.e., cell surviving to several weeks of HER2/EGFR blockade. Interestingly, we observed a marked decrease of cell colonies when pevonedistat was added to persisters survived to three weeks of trastuzumab + lapatinib treatment. These results unveil the possibility of testing in vivo the addition of pevonedistat subsequently to tumor stabilization or reduction by HER2/EGFR blockade, to promote further tumor regression.
Citation Format: Federica Invrea, Alessandro Carugo, Sabrina Arena, Alberto Bardelli, Giulio F. Draetta, Enzo Medico. The NEDD8 pathway as a therapeutic target in HER2-amplified colorectal 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 2611.
Abstract 2612: Depleting EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer
Authors: Yang Lu , Bhattacharya Arup , Li Yun , Sexton Sandra , Ling Xiang , Li Fengzhi , Zhang Yuesheng 
Published: June 2022

Abstract
Background & Goals: Epidermal growth factor receptor (EGFR), an oncogenic receptor tyrosine kinase, is a major therapeutic target in several types of cancers. Several EGFR inhibitors are used to treat EGFR-positive colorectal cancer (CRC). Unfortunately, primary and acquired resistance to the inhibitors is very common. Current approaches to combating the resistance include combining EGFR inhibitors with agent(s) that targets compensatory signaling molecules (HER2, HER3, IGF1R, MET, KRAS, BRAF and PIK3CA). However, responses to such combination treatments are modest, if any. Overcoming drug resistance remains a major unmet medical need in EGFR-positive CRC.
Results: Here, we show the main reason for CRC resistance to EGFR inhibitors and a therapeutic strategy that overcomes it. The sensitivity of CRC cells to EGFR inhibitors correlates with EGFR downregulation. PEPDG278D, a recombinant human protein that induces the degradation of both EGFR and HER2, strongly inhibits oncogenic signaling and growth of CRC in vitro and in vivo (subcutaneous tumors, orthotopic tumors, and patient-derived xenografts), regardless of activating mutations of KRAS, BRAF and PIK3CA. siRNA knockdown of EGFR or HER2 also inhibits CRC cells resistant to EGFR inhibitors. PEPDG278D indirectly suppresses HER3, IGF1R and MET by disrupting their heterodimerization with EGFR or HER2. While excessive tumor-generated EGFR ligands may block target engagement by PEPDG278D, inhibiting ligand shedding by aderbasib enables PEPDG278D to exert strong antitumor activity, and fluorouracil further enhances tumor inhibition. Collectively, our study shows that CRC resistance to EGFR inhibitors result primarily from their inability to eliminate their target and a PEPDG278D-centered combination treatment overcomes the resistance.
Conclusions & Therapeutic Relevance: The therapeutic activity of PEPDG278D highlights that EGFR and HER2 remain indispensable to the survival of CRC cells resistant to EGFR inhibitors. The strong therapeutic activity of PEPDG278D-centered combination treatment in preclinical models of CRC, which carry clinically relevant gene mutations that confer resistance to current EGFR inhibitors, provides the scientific premise for potential evaluation of this recombinant human protein in patients with drug-resistant CRC.
Citation Format: Lu Yang, Arup Bhattacharya, Yun Li, Sandra Sexton, Xiang Ling, Fengzhi Li, Yuesheng Zhang. Depleting EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal 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 2612.
Abstract 2625: Personalized chemotherapy treatments for microsatellite instable tumors
Authors: Hoffman Adam , Pal Sanjima , Sangwan Veena , Ferri Lorenzo 
Published: June 2022

Abstract
Introduction: Esophagogastric adenocarcinomas with microsatellite instability (MSI) high status often display chemoresistance, as the current therapies are ineffective. It is hypothesized that the poor response of MSI-high esophagogastric adenocarcinomas to therapies is due to the extensive genomic mutational heterogeneity, which can be overcome by identifying, stratifying, and targeting multiple genetic alterations concurrently. The goals of this project are to: 1) Identify a matched retrospective cohort of 20 MSI-high to 20 microsatellite stable organoids, derived from biobanked tumor tissue. 2) Analyze mismatch repair protein function/loss, to confirm that the primary tumor microsatellite status is recapitulated in 3D organoid models. 3) Test standard of care chemotherapies, and explore alternative approaches to prevent chemoresistance by evaluating targeted agents based on genomic sequencing.
Methods: Patient-derived organoids grow for ~14 days, after which they are enzymatically disrupted and plated in Matrigel. I will confirm that the organoid models accurately represent clinal response, by treating them with the same chemotherapy received by the patient. 10 different drug concentrations are added in triplicate using a drug dispenser, then after 72 hours, organoid viability is determined with a plate reader.
Results: Genomic characterization of 13/226 MSI-high cases has been conducted with a 234 gene gastric cancer specific panel to identify and target genomic alterations. Preliminary robotic drug screens guided by these mutation profiles have been conducted, yielding promising alternative treatments.
Conclusions: By targeting the particular mutations found in MSI-high patients, it could help explain the chemoresistance mechanism, so promising personalized treatment approaches for esophagogastric adenocarcinomas can be clinically implemented.
Sources of Funding: This project is funded by the Inez and Willena Beaton Award in Oncology, valued at $7,500 and provided by the RI-MUHC. The operating grants that support the research are $120,000 over 2 years from the Cancer Research Society, and $1,200,000 USD over 3 years given by the Department of Defense.
Citation Format: Adam Hoffman, Sanjima Pal, Veena Sangwan, Lorenzo Ferri. Personalized chemotherapy treatments for microsatellite instable tumors [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 2625.
Abstract 2633: Discovery of novel, highly selective inhibitors of PLK4 that demonstrate in vivo regressions in TRIM37 high xenografts
Authors: Edgar Kyle A. , Young Amy , Moore Jared , Chen Xi , Fang Wei , Chang Jae H. , Kong Wayne , Long Jason E. , Pankov Aleksandr , Daemen Anneleen , Shore Daniel G. , Warne Robert , Gibbons Paul , Ndubaku Chudi O. , Junttila Melissa R. , Friedman Lori S. 
Published: June 2022

Abstract
Amplification and copy number alterations of the 17q23 amplicon are common in breast cancer and neuroblastoma and have been associated with early relapse and poor prognosis. Recent work identified a key vulnerability associated with amplicon-driven overexpression of TRIM37 in these tumor types (Meitinger et al. 2020; Yeow et al. 2020). High levels of TRIM37 prevent acentrosomal spindle assembly and render cells mitotically vulnerable to inhibition of polo-like kinase 4 (PLK4), a serine/threonine protein kinase that controls centrosome duplication.
We have discovered potent small molecule inhibitors of PLK4 that are highly selective against the kinome, including against the closely related aurora kinases and PLK1-3. Self-regulation of PLK4 protein levels occurs through proteasomal degradation induced by PLK4 trans-autophosphorylation. ORIC PLK4 inhibitors blocked trans-autophosphorylation leading to stabilization of PLK4, thus directly demonstrating target inhibition in cells. Importantly, PLK4 inhibitor induced PLK4 protein stabilization correlated with cell viability, providing a quantifiable pharmacodynamic (PD) association with antitumor activity. Cell viability assessment across a cancer cell line panel revealed that the highly selective ORIC PLK4 inhibitors showed greater potency in TRIM37 high cancer cell lines as compared to TRIM37 low cell lines. In contrast, less selective compounds, including from the clinical literature, did not display differential potency in TRIM37 high versus low cancer cell lines. Importantly, cell potency in TRIM37 high cancer cells was rescued with knockdown of TRIM37, illustrating that selective PLK4 inhibitors are synthetic lethal with TRIM37 amplification. Oral administration of ORIC PLK4 inhibitors resulted in regressions of TRIM37 high xenograft tumors, with corresponding PD effects and no body weight loss.
In summary, we have discovered novel, potent, highly selective small molecule inhibitors of PLK4 that are orally bioavailable and confirmed the potential for this new target in treating tumors with high levels of TRIM37.
Citation Format: Kyle A. Edgar, Amy Young, Jared Moore, Xi Chen, Wei Fang, Jae H. Chang, Wayne Kong, Jason E. Long, Aleksandr Pankov, Anneleen Daemen, Daniel G. Shore, Robert Warne, Paul Gibbons, Chudi O. Ndubaku, Melissa R. Junttila, Lori S. Friedman. Discovery of novel, highly selective inhibitors of PLK4 that demonstrate in vivo regressions in TRIM37 high xenografts [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 2633.
Abstract 2652: Efficacy of a small molecule MCT1 and MCT4 transporter inhibitor in cancer
Authors: Sharma Sambad , Goreczny Gregory , Bowman Nicole , Duffy Jennifer , Banerjee Daliya , Wijerathna Sanath , Dzuris John , Wu Kerui , Wu Shih-Ying , Tyagi Abhishek , Watabe Kounosuke , Escobedo Jaime , Sandanayaka Vincent 
Published: June 2022

Abstract
Targeting metabolic pathways has been a major clinical interest to effectively treat cancer patients. FDA approval of TIVSOVO(R) (IDH1 inhibitor) has validated the clinical importance of targeting tumor metabolism in cancer. Although MCT1-targeting small molecule inhibitor is currently under investigation for lymphoid cancers, the therapeutic efficacy of this compound is compromised by compensatory overexpression of MCT4 by tumor cells. Therefore, there is a need for a dual MCT1/4 inhibitor to target cancer. We have developed a first-in-class orally bioavailable small molecule inhibitor that targets lactate transport through MCT1 and MCT4 transporters. In 4T1 syngeneic model, we observed a significant dose-dependent reduction of tumor growth by NGY-B treatment that also correlated with serum lactate levels. Immunoprofiling of tumors revealed that NGY-B promoted anti-tumor immune response in 4T1 tumor bearing mice indicating simultaneous immune activation. Also, the combination of NGY-B with a checkpoint inhibitor led to greater efficacy and overall survival in this model suggesting a potential combination therapy in the clinic. Furthermore, we demonstrated the direct tumor cell killing effect of NGY-B in multiple human CDX and PDX models. Therefore, NGY-B intervenes two key hallmarks of cancer - tumor metabolism and anti-tumor immunity, and provides a novel modality to therapeutically target cancer.
Citation Format: Sambad Sharma, Gregory Goreczny, Nicole Bowman, Jennifer Duffy, Daliya Banerjee, Sanath Wijerathna, John Dzuris, Kerui Wu, Shih-Ying Wu, Abhishek Tyagi, Kounosuke Watabe, Jaime Escobedo, Vincent Sandanayaka. Efficacy of a small molecule MCT1 and MCT4 transporter inhibitor in 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 2652.
Abstract 2669: ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models
Authors: Martin Leenus , Lew Erin D. , Patel Roopal , Oh Joanne , Zhang Jingchuan , Nevarez Robin , Congdon Taylor , Lin Wei , Brail Les , Shoemaker Robert 
Published: June 2022

Abstract
KRAS mutations occur in about 25% of all cancers and promote oncogenesis via constitutive activation of the RAS/MAPK pathway. Targeting KRAS mutant tumors by inhibiting individual nodes in the RAS/MAPK pathway, including SHP2, SOS1, KRAS, RAF, MEK, and ERK, has shown early clinical activity, but the rapid emergence of resistance limits the benefit of monotherapy. Resistance is often mediated by reactivation of RAS/MAPK pathway signaling, which can occur by increased activation of upstream of the RAS/MAPK pathway (e.g., EGFR activation) and/or activation of RAS/MAPK pathway nodes (e.g., oncogenic BRAF and MEK mutations). Inhibiting both upstream and downstream RAS/MAPK pathway nodes has the potential to more robustly prevent reactivation relative to inhibition of a single node alone. We are currently exploring the combination of an inhibitor of an upstream node, SHP2, with ERAS-601 and the terminal downstream node, ERK1/2, with ERAS-007 (our first “MAPKlamp”) in nonclinical models. We evaluated this MAPKlamp in NSCLC, CRC, and pancreatic tumor models that harbored KRAS mutations in vitro and in vivo. In 14-day clonogenic assays in KRAS mutant NSCLC, CRC, and PDAC cell lines, this MAPKlamp inhibited colony growth more potently than ERAS-601 or ERAS-007 alone. In KRAS mutant CDX and PDX models, this MAPKlamp’s in vitro activity was observed in vivo where it achieved superior tumor growth inhibition and tumor regression relative to ERAS-601 and ERAS-007 monotherapy. This MAPKlamp showed in vitro and in vivo combination activity in KRAS mutant tumors, and these results support its clinical evaluation in RAS/MAPK pathway-driven tumors.
Citation Format: Leenus Martin, Erin D. Lew, Roopal Patel, Joanne Oh, Jingchuan Zhang, Robin Nevarez, Taylor Congdon, Wei Lin, Les Brail, Robert Shoemaker. ERAS-007 (ERK inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor 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 2669.
Abstract 267: Xenograft models of non-metastatic non-small cell lung cancer reveals micrometastasis-associated single cell composition
Authors: Suvilesh Kanve Nagaraj , Nussbaum Yulia I. , Radhakrishnan Vijay , Manjunath Yariswamy , Avella Diego M. , Staveley-O’Carroll Kevin F. , Kimchi Eric T. , Chaudhuri Aadel A. , Shyu Chi-Ren , Li Guangfu , Pantel Klaus , Warren Wesley C. , Mitchem Jonathan B. , Kaifi Jussuf T. 
Published: June 2022

Abstract
Background: Circulating tumor cells (CTCs) represent micrometastatic disease and may offer unique insights into future recurrences in lethal malignancies, including non-small cell lung cancer (NSCLC). Due to CTC rarity and limited stability, no CTC-derived xenograft (CDX) models have ever been generated from non-metastatic NSCLC patients directly. Alternative strategies are needed to molecularly characterize CTCs in this potentially curable patient group.
Methods: Surgically resected NSCLC primary tumor tissues were implanted in immunodeficient mice to establish ten patient-derived xenografts (PDXs). CTCs from 2/10 PDX models led to generation of two stable metastatic models that were studied by single cell sequencing.
Results: Single cell analysis revealed an additional alveolar epithelial type II (AT2) population in metastatic tumors, besides a common AT2 cluster in PDX/metastatic tumors. This was consistent with an external validation set analysis in primary and metastatic NSCLC patient tumors. Further, AT2 clusters of metastatic tumors expressed higher cancer stemness genes versus primary PDX tumor that was recapitulated in patients primary and metastatic tumors.
Conclusions: Stable metastatic models from early stage NSCLC patients can be generated with CTCs from PDX models. The distinct AT2 population identified in CDX tumors with cancer stemness features might be critical mediator of metastasis that deserves further study to discover personalized strategies against NSCLC micrometastases.
Citation Format: Kanve Nagaraj Suvilesh, Yulia I. Nussbaum, Vijay Radhakrishnan, Yariswamy Manjunath, Diego M. Avella, Kevin F. Staveley-O’Carroll, Eric T. Kimchi, Aadel A. Chaudhuri, Chi-Ren Shyu, Guangfu Li, Klaus Pantel, Wesley C. Warren, Jonathan B. Mitchem, Jussuf T. Kaifi. Xenograft models of non-metastatic non-small cell lung cancer reveals micrometastasis-associated single cell composition [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 267.
Abstract 27: Sex biases in cancer and autoimmune disease incidence are strongly positively correlated with mitochondrial gene expression across human tissues
Authors: Crawford David Robert , Sinha Sanju , Nair Nishanth U. , Ryan Bríd M. , Barnholtz-Sloan Jill , Mount Stephen M. , Erez Ayelet , Adalpe Kenneth , Castle Philip E. , Rajagopal Padma S. , Day Chi-Ping , Schäffer Alejandro A. , Ruppin Eytan 
Published: June 2022

Abstract
Cancer occurs more frequently in men while autoimmune diseases (AIDs) occur more frequently in women. To explore whether these sex biases have a common basis, we collected 170 AID incidence studies from many countries for tissues that have both a cancer type and an AID that arise from that tissue. Analyzing a total of 182 country-specific, tissue-matched cancer-AID incidence rate sex bias data pairs, we find that the sex biases observed in the incidence of AIDs and cancers that occur in the same tissue are positively correlated across human tissues. Second, we find that the sex bias in the expression of the 37 genes encoded in the mitochondrial genome stands out as the common key factor whose levels across human tissues are most strongly and positively associated with these incidence rate sex biases.
Citation Format: David Robert Crawford, Sanju Sinha, Nishanth U. Nair, Bríd M. Ryan, Jill Barnholtz-Sloan, Stephen M. Mount, Ayelet Erez, Kenneth Adalpe, Philip E. Castle, Padma S. Rajagopal, Chi-Ping Day, Alejandro A. Schäffer, Eytan Ruppin. Sex biases in cancer and autoimmune disease incidence are strongly positively correlated with mitochondrial gene expression across human tissues [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 27.