bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4731: Targeting Lon protease as novel strategy to treat aggressive IDH mutant diffuse malignant astrocytoma
Authors: Douglas Christopher , Jain Shashi , Lomeli Naomi , Vu Thao , Pham James , Bota Daniela A. 
Published: March 2024

Abstract
While isocitrate dehydrogenase (IDH) wild-type and mutant malignant astrocytoma (IDHwt, IDHmt) are diffuse CNS tumors that have a high degree of parallelism with one another, including microvascular proliferation and necrosis, the IDHwt tumors clinically presents with a higher tumor grade and thus poorer prognosis and survival rate. Isocitrate dehydrogenase mutation (IDH) hinders the hypoxia response in gliomas and promotes an advantageous reduction in both tumor growth and treatment resistance. Since recurrence is high, adequate characterization and identification of potential novel molecular targets in IDHmt mutant diffuse glioma is integral for developing new therapeutic strategies for better control of tumor burden and, thus, improved outcomes. Our previous published work has shown that the hypoxia responsive LONP1 mitochondrial protease is involved in glioma growth and treatment resistance and that LONP1 inhibitors can augment the effect of chemotherapy in IDHwt models. Here, we highlight the downstream activity of LONP1 via the NRF2 pathway and how synergistically, along with the IDH mutation, LONP1 overexpression can promote the subsequent proneural to mesenchymal transition (PMT) induced by stress and other tumor microenvironment signals. By characterizing the interplay between LONP1 and IDH mutation in in-vitro models, we demonstrate that oxidative stress modulates both PMT and TMZ drug resistance. When translated to an in-vivo patient-derived, intracranial orthotopic xenograft model, LONP1 overexpression is associated with decreased survival.Based on our findings, future clinical translation includes the possibility of using LONP1 as a novel target to optimize the standard of care treatment in IDH mutant diffuse astrocytoma.
Citation Format: Christopher Douglas, Shashi Jain, Naomi Lomeli, Thao Vu, James Pham, Daniela A. Bota. Targeting Lon protease as novel strategy to treat aggressive IDH mutant diffuse malignant astrocytoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4731.
Abstract 4756: Targeting DNA topoisomerase II to manage acquired resistance to third generation EGFR tyrosine kinase inhibitors in the treatment of EGFR mutant NSCLC
Authors: Chen Zhen , Vallega Karin A. , Wang Dongsheng , Quan Zihan , Fan Songqing , Wang Qiming , Leal Ticiana A. , Ramalingam Suresh S. , Sun Shi-Yong 
Published: March 2024

Abstract
Development of effective strategies to manage the inevitable acquired resistance to osimertinib, a 3rd generation EGFR inhibitor with proven clinical efficacy in prolonging survival of patients with EGFR mutant (EGFRm) non-small cell lung cancer (NSCLC), is an urgent and critical area of unmet need in the clinic. Effort toward this direction led us to find that the DNA topoisomerase II (Topo II) inhibitors, doxorubicin and etoposide (VP-16), but not other chemotherapeutic agents, synergistically decreased the survival of osimertinib-resistant cell lines when combined with osimertinib. The combination of osimertinib with either doxorubcin or VP-16 effectively induced DNA damage and apoptosis in osimertinib-resistant cells, suppressed the growth of osimertinib-resistant tumors, and delayed the emergence of acquired resistance to osimertinib. Mechanistic studies found that osimertinib as well other EGFR-TKIs effectively decreased Topo IIα levels in EGFRm NSCLC cells by facilitating its proteasomal degradation and induced DNA damage; these effects were lost in cell lines with osimertinib acquired resistance that possessed elevated basal levels of Topo IIα. In the majority of EGFRm NSCLC tissues relapsed from EGFR-TKI treatment, Topo IIα levels were substantially increased. Enforced expression of ectopic TOP2A genes in sensitive EGFRm NSCLC cells conferred resistance to osimertinib in inducing DNA damage and apoptosis, whereas knockdown of TOP2A in osimertinib-resistant cell lines restored their responses to undergo osimertinib-induced DNA damage and apoptosis. Together, these results reveal a previously undiscovered essential role of Topo IIα modulation in regulating the responses of EGFRm NSCLC cells to osimertinib, providing scientific rationale for targeting Topo II to manage acquired resistance to osimertinib and possibly other third generation EGFR-TKIs, thus warranting clinical validation of this strategy. (This study was supported by NIH/NCI R01 CA223220 and UG1 CA233259 and Emory Winship Cancer Institute lung cancer research pilot funds).
Citation Format: Zhen Chen, Karin A. Vallega, Dongsheng Wang, Zihan Quan, Songqing Fan, Qiming Wang, Ticiana A. Leal, Suresh S. Ramalingam, Shi-Yong Sun. Targeting DNA topoisomerase II to manage acquired resistance to third generation EGFR tyrosine kinase inhibitors in the treatment of EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4756.
Abstract 4757: Combining PARP inhibitor with TACC3 inhibition overcomes PARP inhibitor resistance in ovarian cancer
Authors: Wu Yu , Wang Qilong , Deng Chaolin , Li Mo , Xiao Yinan 
Published: March 2024

Abstract
The treatment of ovarian cancer (OC) presents a significant challenge due to the emergence of resistance to poly (ADP-ribose) polymerase inhibitors (PARPi). Transforming acidic coiled coil containing protein 3 (TACC3) belongs to the TACC family, characterized by its coiled-coil domains. TACC3 plays a crucial role in cell division, particularly in the formation and stability of the mitotic spindle, which is essential for proper chromosome segregation. Mutations or changes in TACC3 have been associated with various cancers, making it an increasingly attractive target for anticancer therapy in recent years. Here, we demonstrated a significant upregulation of TACC3 in OC, correlating with adverse clinical outcomes. Notably, PARPi-resistant OC cells exhibited a marked sensitivity to TACC3 inhibition. This was evidenced by the induction of spindle defects and mitotic catastrophe in PARPi-resistant cells upon TACC3 suppression, achieved either genetically or pharmacologically. Moreover, we explored the therapeutic efficacy of combining TACC3 inhibitor with PARPi, specifically BO-264 with olaparib or niraparib. This combination exhibited a synergistic effect, markedly reducing cell viability in vitro and tumor growth in PARPi-resistant tumor xenograft models. Our study suggests a promising new method for treating ovarian cancer, especially for those resistant to current PARPi treatments, by simultaneously targeting TACC3 and PARPi, enhancing treatment efficacy and potentially improving patient outcomes.
Citation Format: Yu Wu, Qilong Wang, Chaolin Deng, Mo Li, Yinan Xiao. Combining PARP inhibitor with TACC3 inhibition overcomes PARP inhibitor resistance in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4757.
Abstract 4767: Changes in the NSE and S100B levels following treatment with peripheral neuropathy-inducing drugs
Authors: Vontikommu Priya R. , Selvakumar Shriya , Natarajan Umamaheshwari , Rathinavelu Appu 
Published: March 2024

Abstract
Neo-adjuvant chemotherapy is considered the standard of care for patients with multiple myeloma (MM). Peripheral neuropathy (PN) is one of the most common chemotherapy-induced side effects that impact 50% of all patients who receive chemotherapy and can lead to discontinuation of drug treatment. Treatment with Bortezomib (BTZ), Cisplatin (CIS), and Vincristine (VIN) has been established as the most common trigger of Chemotherapylnduced Peripheral Neuropathy (CIPN) among cancer patients. Since CIPN can lead to disabling long-term adverse effects, many cancer patients discontinue or limit their treatment regimen once they see signs or symptoms of CIPN. Therefore, it was hypothesized that developing diagnostic/prognostic biomarkers that can accurately predict the onset or progression of CIPN would help to determine the chemotherapy eligibility with the above-mentioned drugs and proactively prepare for protective care. Hence, our initial goal was to elucidate the molecular mechanisms underlying the onset and progression of CIPN that would allow for the identification of suitable biomarkers that can be used for monitoring before or during chemotherapy with BTZ, CIS, and VIN. Initially, we conducted in vitro studies to identify the underlying molecular mechanisms activating CIPN related pathways. We used neuronal Schwann cells (RT4), for testing the neurotoxic effects of BTZ, CIS, and VIN that might precede or coincide with the onset of CIPN in an in vivo condition. Interestingly, the BTZ treatment was able to significantly reduce the intracellular level of NSE and S100B in RT4 cells compared to the untreated controls, when they were measured using an immunofluorescence assay and Western blot. Furthermore, we conducted an in vivo study to determine the CIPN using rats. We used the sciatic nerve (SN) from drug-treated animals to check the S100B level using the ELISA method. Our preliminary results showed that levels of S100B in the SN of Rats were reduced following 8 weeks of treatment with the PN-inducing chemo drugs. We anticipate that this study will enrich our understanding of how chemotherapy medications induce PN in cancer patients and guide us to identify reliable biomarkers (This project was supported by the PFRDG grant of the Nova Southeastern University, Ft. Lauderdale Florida, and the Royal Dames of Cancer Research Inc., Ft. Lauderdale, Florida).
Citation Format: Priya R. Vontikommu, Shriya Selvakumar, Umamaheshwari Natarajan, Appu Rathinavelu. Changes in the NSE and S100B levels following treatment with peripheral neuropathy-inducing drugs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4767.
Abstract 4786: Colorectal cancer screening rates among deaf, deafblind, and hard of hearing adults aged 45 to 75 years old
Authors: Wang Regina M. , Rao Sowmya R. , Bergeron Erika J. , Perrodin-Njoku Emmanuel C. , Kushalnagar Poorna 
Published: March 2024

Abstract
Background: Deaf, deafblind, and hard of hearing (DDBHH) individuals who use American Sign Language (ASL), a subpopulation of the disability, experience disparities concerning cancer screening and cancer-related health outcomes. For this study, we explored colorectal cancer screening rates among DDBHH survey respondents in comparison to rates found in the hearing population.
Materials and Methods: Using the National Cancer Institute Health Information National Trends Survey in ASL (Kushalnagar et al., 2015), we surveyed participants 18+ years old using the Center for Deaf Health Equity at Gallaudet University’s database of over 2,500 DDBHH participants from all over the USA, including Hawaii and Puerto Rico. We used the U.S. Preventive Services Task Force (USPSTF) guidelines’ age cutoffs to assess adherence to colorectal cancer screenings.
Results: Survey response rate within three weeks of mail out in July 2023 was 12%. A total of 405 DDBHH adult participants answered screening questions for colorectal cancer in ASL and English. Overall, 43.7% self-reported screening adherence for age-eligible (45-75 years) colorectal cancer screening; 54.7% reported never having a colorectal cancer screening. Similarly-aged hearing adults reported 58.7% adherence in the English version of the National Health Interview Survey (NHIS).
Discussion: With the 43.7% adherence rate, the DDBHH community is lagging behind colorectal cancer screenings compared to the general population of hearing adults. Estimating the colorectal cancer screening rates among the DBHH community and understanding the reasons for these existing disparities is important to achieve screening adherence of 68.3%, the target set by the Healthy People 2030. Such research will aid the Center for Deaf Health Equity to actively work with the community to improve strategies to increase colorectal cancer screening.
Citation Format: Regina M. Wang, Sowmya R. Rao, Erika J. Bergeron, Emmanuel C. Perrodin-Njoku, Poorna Kushalnagar. Colorectal cancer screening rates among deaf, deafblind, and hard of hearing adults aged 45 to 75 years old [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4786.
Abstract 4808: Small intestinal leiomyosarcoma in a young adult
Authors: Guo Alyssa A. , Bentley Blake H. , Ellington Abigail L. , Lu Haiyan , Lippert William C. 
Published: March 2024

Abstract
Objectives: • Outline the epidemiology of leiomyosarcoma•Identify the immunohistochemistry of a leiomyosarcoma
Introduction: Primary small intestinal malignancies are rare malignancies as compared with other malignancies of the gastrointestinal tract. Here, we present a case of a jejunal leiomyosarcoma in a young adult.
Case Presentation: A 23-year-old Caucasian male with GERD presented with five months of abdominal pain, intermittent nausea with non-bloody emesis, and a 20-pound weight loss. Presenting vital signs were within normal limits. Physical exam revealed conjunctival pallor with epigastric tenderness to palpation. Serology demonstrated iron deficiency anemia, hemoccult positive stool, negative CEA, CA19-9, and AFP tumor markers. HIV antigen antibody and EBV-PCR were non-reactive. CT of the abdomen and pelvis revealed markedly thickened heterogenous jejunal loop in the left hemiabdomen with associated mesenteric adenopathy and small volume pelvic ascites. EGD with push enteroscopy revealed a single, malignant appearing and ulcerated mass in the proximal jejunum. PET-CT showed a hypermetabolic, multilobulated, ill-defined mass involving multiple loops of jejunum. He underwent exploratory laparotomy with resection of a proximal jejunal mass (10x8 x7 cm), mesenteric lymphadenectomy, and a jejunojejunostomy creation. Pathology demonstrated leiomyosarcoma (pT2aN0MoG3), and he was initiated on cyclophosphamide and doxorubicin.
Discussion: Primary small intestinal malignancies are rare malignancies with an incidence of less than 5% of all GI malignancies. 56 cases of GI leiomyosarcoma in adults were identified between 2000-2012 with a peak incidence between 55-59 years of age (Aggarrwal 2012). Leiomyosarcomas are soft tissue sarcomas arising from bones, tendons, blood vessels, or muscles with a spectrum of disease ranging from low-grade cutaneous lesions to aggressive lesions of internal organs with significant potential for metastasis (Pipe 2002). Diagnosis is based on immunohistochemical positivity for SMA, desmin, and h-caldesmon, and negativity for CD117, CD34, and DOG1.1, notably lacking KIT and PDGFRA mutations (Aggarwal 2012). Treatment involves surgical resection and a cost benefit analysis of adjuvant chemotherapy with (Reynolds, 2014). This case of a 23 year old, without significant risk factors, diagnosed with a jejunal leiomyosarcoma presents as one of the youngest cases ever to be reported and emphasizes the importance of recognizing the cancer in a broader range of the adult population.
Citation Format: Alyssa A. Guo, Blake H. Bentley, Abigail L. Ellington, Haiyan Lu, William C. Lippert. Small intestinal leiomyosarcoma in a young adult [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4808.
Abstract 4816: Racial disparities in adjunctive supportive care medication use in pancreatic cancer patients
Authors: Kweyete Olga M. Trejos , Guo Yi , Rogers Sherise C. , Scarton Lisa , DeRemer David L. , Whitner Chardae L. , Wilkie Diana J. , Allen John M. 
Published: March 2024

Abstract
Background: Beyond its well-known lethality, pancreatic cancer (PC) is associated with a wide variety of physical and psychological complications. These complications collectively lead to an increase in symptom burden experienced by patients with PC, as compared to other cancer types, leading to lower health-related quality of life (HRQoL) and worsened clinical outcomes. Reducing symptom burden is often achieved through the use of supportive care medications (SCM). Racial disparities have been described in the use of pain and psychiatric medications but limited research has explored potential disparities in access to and utilization of other SCM among diverse racial and ethnic groups. The goal of this study was to illustrate the presence of racial/ethnic disparities in the treatment patterns of supportive care medications in end-of-life care of PC patients
Methods: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database from 2005 to 2017. Participants were identified using ICD9 and ICD10 diagnostic codes. Patients diagnosed with PC and have died in 2005-2007 with more than 1 year of Medicare enrollment before death were included. Logistic regression models to assess the association between use of supportive care medications and race, adjusting for covariates (sex, race, age, marital status, education, income, residence, CCI, year of diagnosis of PC, cancer stage).
Results: After the application of the inclusion/exclusion criteria, 74,309 patients were included in the final analysis (White: 72.53%, Black 11.01%, Hispanic 9.60%, Asian/Pacific Islander 6.58%) Racial and ethnic disparities in the use of multiple SCM drug classes were identified. The results are summarized in Table 1.
Conclusion: Disparities in the use of SCM were found in patients with PC. Minorities had significantly less use of sleep aids and headache aids, and increased use of cognitive aids and appetite stimulants. AAs also had lower uses of anti-emetics.
AA Hispanic Asian SCM Drug Class aOR 95% CI aOR 95% CI aOR 95% CI Anti-emetics 0.77 (0.73, 0.81) 0.98 (0.93, 1.03) 1.01 (0.95, 1.08) Appetite stimulants 1.06 (1.01, 1.11) 1.01 (0.96, 1.06) 1.28 (1.20, 1.36) Cognitive aids 1.38 (1.25, 1.53) 1.04 (0.93, 1.17) 1.11 (0.97, 1.26) Headache aids 0.68 (0.63, 0.74) 0.81 (0.74, 0.87) 0.85 (0.77, 0.93) Sleep aids 0.71 (0.67, 0.75) 0.87 (0.82, 0.92) 0.87 (0.81, 0.93)
Citation Format: Olga M. Trejos Kweyete, Yi Guo, Sherise C. Rogers, Lisa Scarton, David L. DeRemer, Chardae L. Whitner, Diana J. Wilkie, John M. Allen. Racial disparities in adjunctive supportive care medication use in pancreatic cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4816.
Abstract 488: Modulation of ENPP1 activity and 2'3'-cGAMP degradation in ovarian cancer cell lines via loadable pre-formed lipid nanoparticles
Authors: Taylor David , Ji Jiajia , Rzeczycki Phillip , Collins Margaret L. , Clements Lauren , Ariosa Aileen R. 
Published: March 2024

Abstract
Ovarian cancer is a complex heterogeneous disease with various subtypes and diverse molecular mechanisms of pathogenesis. Among different forms, epithelial ovarian cancer is the most common, representing up to 90% of total reported cases. Due to the lack of early diagnostic tools, the prognosis is mainly poor, as most cases are typically identified in advanced stages. Thus, a more thorough understanding of the inherent complexities of the disease, in terms of its biochemical etiology, will allow for identification of specific molecular and genetic profiles that could lead to more effective treatment plans. Recent studies have shown that ENPP1 may play a role in cancer cell proliferation, migration, and invasion in ovarian and other types of cancer. ENPP1 is a glycosylated type II transmembrane protein acting as a pyrophosphatase and phosphodiesterase with broad specificity. ENPP1 substrates include mononucleotides and cyclic dinucleotides such as the second messenger, 2'3'-cGAMP, which binds to and activates STING. 2'3'-cGAMP is exported extracellularly by cancerous cells into the tumor microenvironment where uptake into neighboring cells can activate their STING-dependent type 1 interferon pathway and promote antitumoral immune responses. ENPP1 can hydrolyze extracellular 2'3'-cGAMP however, allowing cancer cells to evade such an immune response. In this study, we assessed the activity of ENPP1 in CaOV-3, SK-OV-3, and PA-1 ovarian cancer cell lines using a fluorometric cell-based assay. The effects of ENPP1 inhibition via a chemical inhibitor on extracellular 2'3'-cGAMP levels were characterized and compared with siRNA-mediated knockdown of ENPP1 via loadable pre-formed lipid nanoparticles, which enable small-scale encapsulation and transfection of nucleic acid cargo. In addition, we explored whether uptake of exogenous 2'3'-cGAMP into THP-1 and RAW immune cell lines can be enhanced through delivery via preformed loadable lipid nanoparticles. Corresponding immune cell activation was also assessed using immunoblotting and RT-PCR. Our results demonstrate how modulation of ENPP1 activity and 2'3'-cGAMP levels in ovarian cancer cell lines using unconventional, pre-formed loadable lipid nanoparticle transfection reagent can aid in elucidating mechanisms of immune evasion in cancer cells.
Citation Format: David Taylor, Jiajia Ji, Phillip Rzeczycki, Margaret L. Collins, Lauren Clements, Aileen R. Ariosa. Modulation of ENPP1 activity and 2'3'-cGAMP degradation in ovarian cancer cell lines via loadable pre-formed lipid nanoparticles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 488.