bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reporting an Indian multicentric community oncology practice’s observation on patterns of homologous recombinant deficiency across various solid cancers evaluated through tumor-DNA-based NGS.
Authors: Bose Chirantan , Maheshwari Udip , Morzaria Dr Disha , Joshi Ashish , Maniar Vashishth , Jobanputra Kunal Naishadh , Pawar Akash , Joshi Kshitij Chandrakant , Kalaskar Pritam , Mekha Mangesh , Chaudhari Krushna , Sethjiwala Taha , Pal Devendra , Sheth Smit , Khandare Pravin 
Published: June 2024

e15066 Background: Homologous recombinant deficiency(HRD) is being evaluated across various solid organ malignancies to assess not just the underlying biological behavior of the cancer but also for potential response to PARP inhibitors. HRD status is assessed by measuring mutations in genes involved in the HRR (Homologous Recombinant Repair) pathway along with other genomic aberrations across the tumor genome like Loss of Heterozygosity (LOH), Telomeric Allelic Instability (TAI) and Large Scale Transitions (LST).We compare here overall HRD scores and their sensitivity and specificity to HRR v/s HRR + LOH, TAI, and LST in an attempt to study the prevalence and pattern of HRD scoring and response to PARPi. Methods: The retrospective data of cancer patients who have undertaken the aforementioned test were evaluated to analyze the patterns of HRD. Responses of a limited subset of patients who received PARP inhibitors were also assessed. Results: A total of 101 patients were evaluated from a community oncology practice over the last 1 year who underwent HRD testing of which 58.4% were female and 41.5% were male. 27.7% of patients were therapy-naive of which 67.8% were stage IV, 28.5% were stage III, and 3.5% were stage I/II while 72.2% were pre-treated and mostly ( > 90%) of advanced stage. The most common cancer types that were tested were Gynaecological cancers (20.7%), followed by Pancreatobiliary (18.8%), Lung (13.8%), Genitourinary (13.8%), and other solid cancers (32.4%). Limited-HRD testing based on small panel HRR genes was performed on 9.9% (10/101) while Comprehensive-HRD (including HRR genes, LOH, TAI, and LST) was performed on 90% (91/101). The sensitivity and specificity of Limited-HRD were 43.75% (with 95% CI 26.36% to 62.34%) and 69.46% (with 95% CI 56.13% to 80.81%) showing an accuracy of 60.44% (with 95% CI 49.64% to 70.54%). Comprehensive-HRD analysis showed a sensitivity of 78.12% (60.03% to 90.72%) and specificity of 67.80% (54.36% to 79.38%) with increased accuracy of 71.43% (with 95% CI 49.64% to 7.54%) as compared to Limited-HRD. PARPi were used in 8.9% (9/101) of patients for organ types- Ovary (44.4%), Prostate (33.3%), Stomach (11.1%), and Lung (11.1%) with a clinical benefit rate of 66.6%. It is also reported that in 3% of cases, BRCA1 mutation was detected however, the comprehensive-HRD score was found low. Conclusions: Predictive sensitivity and accuracy improved with Comprehensive-HRD analysis, thereby reflecting the power of LOH, TAI, and LST in the true identification of both positive and negative cases thus expanding the usage of PARPi in deserving patients.
Patient-derived 3D bioprinting pan-cancer drug screening platform for personalized medicine.
Authors: Yang Huiyu , Zhang Jiangang , Shan Ying , Wang Yanan , Cao Yaning , Sun Yuning , Jin Ying , Pan Lingya , Ke Chunhai , Cui Wei , Yang Mian , Zhou Bo , Jia Ziqi , Cao Heng , Wang Yu , Ma Wenbin , Xu Xiao , Zhao Hai-Tao , Yang Huayu , Mao Yilei 
Published: June 2024

e15088 Background: Patient-derived tumor model offers an individualized approach to overcome interpatient heterogeneity in cancer therapy. 3D bioprinting (3DB) enables construction of in vitro model with high-throughput, high-fidelity, and high efficacy. We hereby report a pipeline of establishing pan-cancer patient-derived 3DB (PT-3DB) models with personalized drug sensitivity results in 148 patients from multiple medical centers. Methods: Tumor tissues of 148 patients were collected with informed consent at 4 medical centers in Beijing, Hangzhou and Ningbo from 2022-12 to 2023-12. Tumors were digested into cell suspension and mixed with GelMA, and PT-3DB was fabricated by extrusion-based bioprinter. A panel of chemotherapies and targeted therapies was selected based on first-line treatment of corresponding cancer type. PT-3DB was treated with drugs in dose gradient at DIV 5. Cell viability was measured by ATP quantification at DIV 8 and dose-response curve and IC50 of each drug was calculated. Results: We have established PT-3DB in 148 patients with success rate of > 95% and turnaround time of only 8 days. 137 were surgically resected samples and 11 were biopsy samples. Cancer types included ovarian cancer (OC, n = 52), colorectal cancer (CRC, n = 51), hepatobiliary cancer (HBC, n = 17), breast cancer (BC, n = 10), high-grade glioma (HGG, n = 10), cervical cancer (CC, n = 4), pancreatic cancer (PC, n = 2), and gastric cancer (GC, n = 2). A total of 27 drugs were screened, of which 15 were chemotherapies and 12 were targeted therapies. The median number of drugs tested for each patient was 5 (4-6) (Q25-Q75). Significant interpatient heterogeneous drug response was observed within each cancer type and between tumors with the same treatment regime. Representative data were presented in the attached table. Conclusions: We have successfully constructed pan-cancer PT-3DB platform for personalized drug screening in 148 cases, with outstanding stability across multiple centers. The timeline of 8 days preceded pathological diagnosis, which is the earliest start of systematic treatment, underscoring its high translational potential. PT-3DB has demonstrated interpatient heterogeneous response to systematic treatment, providing a strong foundation for precision medicine. Our ongoing research aims to correlate PT-3DB drug responses with clinical outcomes. [Table: see text]
Study on the mechanism of ginsenoside Rg5 attenuating radiation myocarditis through GDF11-SIRT1 pathway.
Authors: Bai Hansong , Li Tao 
Published: June 2024

e15098 Background: Radiation-induced Heart Disease (RIHD) refers to the damage caused by the radiation dose to the heart during radiotherapy for malignant tumors (especially chest tumors), generally including myocardial disease, pericardial disease, coronary artery disease, etc. It generally occurs during radiotherapy or within months to years after radiotherapy. It is reported that the incidence within 5-10 years after the end of radiotherapy is about 10%-30%. With the advancement of equipment and technology, radiotherapy has become increasingly involved in malignant tumors and has become one of the most important treatments for thoracic tumors. Radiation heart disease will significantly reduce the quality of life of patients with malignant tumors after radiotherapy. and survival rate. Although the incidence of RIHD can be reduced by optimizing radiotherapy technology, current technology cannot eliminate the risk of RIHD4. Therefore, it is of great clinical significance to explore how to reduce the incidence and severity of radiation heart disease. Methods: In vitro cultured cardiomyocyte model: used to analyze the impact of Rg5 on cardiomyocytes at the molecular level. Animal model: Construct an animal model of radiation heart disease to evaluate the protective effect of Rg5. Construction of iPCS organoid model to verify that Rg5 attenuates radiation heart disease mediated through Sirt1. Results: Immunohistochemistry, HE staining and Masson staining in early animal experiments showed that Rg5 can slow down radiation heart disease caused by radiotherapy. Immunohistochemistry results showed that SIRT1, HDAC3, PINK1, PARKIN, MFN2 and GDF11 showed obvious differences in expression, while SIRT6 and DRP1 did not. There were obvious differences. At the same time, immunofluorescence double staining of DRP1+SIRT1, MFN2+SIRT1, and HDAC3+SIRT1 was further performed to clarify their intracellular spatial relationship. After using iPSCs to induce cardiac endothelial cells, double immunofluorescence staining of mitochondrial markers and endothelial marker CD31 was performed. The results showed that radiotherapy can cause damage to vascular endothelial cells, reduce vascular integrity, reduce mitochondrial length, and impair function. Ginsenoside Rg5 can reduce this trend. From the common database of single-cell myocardial tissue, it was found that markers such as SIRT1, HDAC3, PINK1, MFN2, GDF11, and GPX4 have similar expression profiles in cardiomyocytes and are more likely to regulate each other. Conclusions: Ginsenoside Rg5 can regulate cardiac radiation injury through the HSP90α-HDAC3-GDF11-SIRT1 axis.It is expected to provide new therapeutic targets for the prevention and treatment of radiation heart disease, making ginsenoside Rg5 of great value in radiotherapy sensitization and radiation heart protection.
Pharmacogenomic diversity of clinically significant cancer treatment biomarkers in ancestrally diverse US population.
Authors: Fonkem Ekokobe , Aminkeng Folefac , Hay Chuck , Al-Gizawiy Mona M , Pettit Jaimy , Connelly Jennifer M , Schmainda Kathleen M 
Published: June 2024

e15099 Background: Cancer Health Disparities (CHD), in the US is well documented. The is significant evidence of CHD treatment related outcomes along ancestry lines. Africans and Hispanics generally have higher rates of adverse drug reactions (ADR), and poorer survival and response rates when compared to Europeans and Asians. The causes of CHD treatment related outcomes are poorly understood but it is plausible to believe that CHD has a genetic basis, given that human genomic variations underlie both disease susceptibility and treatment outcomes. Our goal is to determine the genetic basis of CHD treatment related outcome, with a particular focus on under-represented and underserved populations. Methods: We will deploy pharmacogenomic (PGx) differentiation analyses using a comprehensive patient database and correlative banked tissue (~ 2,000 patients) from MCW, together with 3 international cohorts as comparators (Africans = 372, Asians = 1,250 and Europeans = 958) to: Interrogate clinically significant cancer treatment PGx biomarkers and characterize the variation across different populations. Assess the implications of genetic admixture on CHD treatment related outcomes. Evaluate the intersection of genetic diversity with pharmacogenomic diversity. Explore the distribution of age, gender, diagnosis, treatments, response, ADRs, survival, comorbidities, and concomitant medication. Results: Our initial results point to a significant genetic contribution to CHD treatment related outcomes. The enrichment of genetic risk factors for therapeutic failure, ADRs or poorer survival in patients of African vs European descent, explains the increased sensitivity to ADRs, poorer response rates, and decreased survival in patients of African vs European descent. We will extend this analysis to a multi-ethnic US cohort including Africans, Hispanics, Europeans, Asians, and First Nations. Conclusions: There is extensive PGx diversity within the US population, hence, coupling preemptive PGx testing with genetic testing is imperative for a truly equitable delivery of healthcare. There is a need for diversified representation of all population in cancer research to level the gaps in CHD. The identification of the genetic basis of CHD treatment related outcomes is imperative for predicting outcomes, and the implementation of preemptive PGx and precision medicine. [Table: see text]
Phase 1 study of ERK inhibitor JSI-1187 for patients with advanced solid tumors with MAPK pathway mutations.
Authors: Xi Yuqin , Wang Zhenghang , Shen Lin , Wu Lin , Chen Yu , Fang Meiyu , Li Mei , Ye Feng , Paradiso Linda J. , Myers Thomas J. , He Junqiang , Zhang Jintao , Xu Wen , Zhang Lei , Li Ao 
Published: June 2024

e15111 Background: Mitogen-activated protein kinase (MAPK) pathway is a key regulator of cellular proliferation and survival, it is highly correlated with the occurrence of many cancers, JSI-1187 is a potent and reversible small molecule inhibitor of ERK1/2. This study is designed to assess the safety and efficacy of ERK Inhibitor JSI-1187 for advanced MAPK-mutant tumors patients. Methods: This is a phase 1 study included dose escalation and expansion (NCT06239623). The dose escalation study was conducted using a 3+3 escalation design to assess JSI-1187 16, 24, 32, 48,72, 80 and 96 mg BID, and 80, 128 and 152mg QD, repeated q 28 days. Dose limiting toxicities (DLTs) were predefined in the protocol. MAPK-mutant tumor patients whose disease progressed after existing standard treatment were treated. RAS and BRAF-mutated solid malignant tumors were explored in the dose-escalation phase. Results: As of December 23, 2023, 26 patients were enrolled, including 23 from the BID group and 3 from the 80mg QD group. No DLT was observed in QD group, 1 DLT (1 macular edema) and 2 DLTs (1 macular edema and 1 pneumonia) were observed at 96 and 80 mg BID, respectively. The most common JSI-1187 16-96mg BID related AEs were hypoalbuminemia (69.6%), rash (62.5%), and anemia (43.5%), while the most common JSI-1187 80mg QD related AEs were rash (100%), leukopenia (100%) and neutropenia (66.7%). The most common Grade 3 JSI-1187 16-96mg BID treatment-related AEs were anemia (17.4%) and thrombocytopenia (8.7%). Tumor response was evaluated in 18 of the total 26 patients. SD was noted as best response at doses of 16 – 96 mg BID and 80 mg QD including 29.8% tumor shrinkage in 1 NRAS-mutant melanoma patient treated at 32mg BID and 21.6% tumor shrinkage in 1 MEK1 K57N-mutant lung cancer patient treated at 72mg BID. Conclusions: JSI-1187 monotherapy is well-tolerated in advanced solid tumor patients and demonstrated preliminary antitumor effect. Current evidence supports future exploration of JSI-1187 as monotherapy, and in combination, in patients with MAPK-mutant tumors. Research Sponsor: JS Innopharm Clinical trial information: NCT06239623 .
Phase I clinical study of FC084CSA, a high selective AXL kinase inhibitor that ameliorates tumor microenvironment and augments the effectivity of immunotherapy.
Authors: Li Wei , Wang Lei , Wang Jing , Song Zhengbo , Zhang Qingyuan , Zhou Caicun 
Published: June 2024

e15116 Background: NSCLC patients with STK11 gene mutations could not benefit from immunotherapy, according to the data of multiple clinical trials. This is associated with immunosuppressive tumor microenvironment (TME) due to elevated AXL expression, and deficiency in pro-inflammatory cytokines and effector T cells. AXL inhibitor bemcentinib (formerly BGB324) has been found to improve the effectiveness of immunotherapy of immune checkpoint inhibitors. FC084CSA is a high selective AXL inhibitor. Methods: This is an ongoing first-in-human, phase I study of FC084CSA in patients with advanced solid tumors. The primary objective is to evaluate the safety and tolerability of FC084CSA. The secondary objectives include preliminary efficacy and pharmacokinetics. Results: As of January 10th, 2024, 9 patients with a median age of 60 years (44-73) were enrolled in 4 different dose levels: 100mg QD, 200mg QD, 400mg QD and 600mg QD. All patients had ≥ 2 prior lines of prior therapy. No dosing-limiting toxicities were observed. 8 (88.9%) patients experienced treatment-related adverse events (TRAEs). Most TRAEs were grade 1 or 2 and only one grade 3 TRAE was observed. The most common TRAEs (≥20%) included increased blood lactate dehydrogenase (44.4%), elevated gamma-glutamyl transferase (33.3%), proteinuria (33.3%), anemia (33.3%), increased aspartate aminotransferase (22.2%), weight loss (22.2%), increased blood creatinine (22.2%) and vomiting (22.2%). A total of 8 patients had at least 1 post-baseline tumor assessment. Objective response rate (ORR) was 0% and disease control rate (DCR) was 62.5% (5/8). Conclusions: FC084CSA was well tolerated in patients with previously heavily treated solid tumors. Clinical trial information: NCT06231550 .
Safety, efficacy, pharmacokinetics, and pharmacodynamics of the illudofulvene drug CAP-0121.
Authors: Suhandynata Raymond T. , Nguyen TK , Kotamraju Venkata R. , Momper Jeremiah D , Kelner Michael J. 
Published: June 2024

e15120 Background: Irofulven is an anticancer agent derived from illudin S initially investigated due to its unique mechanism of action and potential to overcome multi-drug resistance. This study investigates the pharmacokinetics/pharmacodynamics (PK/PD) and efficacy and safety of the second-generation drug, CAP-0121 (Califia Pharma). Methods: 24-hour comprehensive PK was performed at two different intravenous (IV) doses in canines for irofulven (0.2 mg/kg and 1 mg/kg; MTD) and CAP-0121 (1 mg/kg and 3 mg/kg). Plasma concentrations were measured by LC-MS/MS and PK parameters were calculated for both drugs using noncompartmental methods (Phoenix WinNonlin, version 8.4). PK parameters included area under the concentration vs time curve (AUC), maximum observed concentration (Cmax), clearance (CL), volume of distribution (Vd), and elimination half-life (t1/2). Canine chemistry/hematology/coagulation/urine panels, were measured across 28 days to ascertain the maximum tolerated dose (MTD). Both platelet and neutrophil count reversibility was also assessed. Mice xenograft models implanted with a drug resistant human ovarian cancer (A2870), or a drug-resistant human metastatic lung cancer (MV522), were dosed with irofulven (9 mg/kg; MTD) and CAP-0121 (15, 20, and 25 mg/kg) and resulting tumor mass, % change in body weight, and platelet counts were compared relative to vehicle only. Results: Systemic exposure, CL, Vd, and t1/2 were similar between irofulven and CAP-0121 at a 1 mg/kg IV dose. For irofulven, AUC increased approximately proportionally at doses of 0.2 mg/kg and 1 mg/kg. For CAP-0121, exposure also increased proportionally at doses of 1 mg/kg and 3 mg/kg. MTD of CAP-0121 was found to be 3-fold higher in canines compared to irofulven as 3-fold more CAP-0121 was required to match the platelet reduction observed with irofulven; platelet and neutrophil nadir was rapidly reversible for CAP-0121. Canine nadir platelets and neutrophil counts were 3-fold higher for CAP-0121 vs irofulven at the same dose (1 mg/kg). There was no evidence of any canine systemic organ toxicity (gross, histologic, blood and urine analysis) for CAP-0121 at either dose. CAP-0121 was superior to irofulven (p < 0.02) with regards to final tumor weights in mice xenograft models, even though MTD was not reached for CAP-0121; a change in body weight and platelet loss was not observed for CAP-0121 at up 25 mg/kg in mice. With regards to in vitro anticancer cytotoxic activity, the two drug-resistant xenograft models confirm the superiority of CAP-0121 over irofulven. This study demonstrates that CAP-0121 has favorable PK parameters and a wider therapeutic window in humans compared to irofulven, emphasizing the potential anticancer utility of CAP-0121 for solid cancers without prolonged thrombocytopenia. Conclusions: Further investigation in clinical trials is warranted to confirm these preclinical observations.
Characterization of novel compounds that directly bind to and inactivate the HPV E6 protein for treatment of HPV-associated cervical and oropharyngeal cancers.
Authors: Nichols William Garrett , Rietz Anne , Kumari Lokesh , Lu Zhijian , Androphy Elliot 
Published: June 2024

e15122 Background: The human papillomavirus (HPV) E6 protein is necessary for viral genome replication and is always expressed in HPV-induced malignancies. We performed in silico screening of chemical libraries for molecules that bind to a pocket on the cancer associated HPV-16 E6 protein. We focused on the protein-protein interaction of E6 with one of its cellular binding partners, the ubiquitin ligase E6AP. In a trimolecular complex with E6, E6AP ubiquitinates p53, leading to its destruction by the proteasome. We designed, synthesized, and characterized >300 compounds that 1) bind to the E6AP interaction surface of the HPV-16 E6 protein; 2) are armed with a ‘warhead’ to make an irreversible bond with a specific cysteine in this HPV-16 E6 binding pocket; 3) and restore levels of p53 and selectively decrease viability of HPV-16 expressing tumor derived cells. Methods: E6 inhibitor optimization was guided by in silico docking strategies, co-crystallization, and medicinal chemistry, followed by biochemical and cellular assays to iteratively design and synthesize molecules with increased E6 inhibitory activities. Results: We used whole protein mass spectrometry to interrogate covalent bonding to E6, showing irreversible binding to the cysteine in the targeted E6 binding pocket without the other 13 cysteines in E6, with Ki in the range of seconds. Biolayer interferometry and fluorescence polarimetry measured blockade of E6 with E6AP, with IC50 in the range of 400-600 nM. To establish in cell inactivation of E6, human cervical cancer derived SiHa cells that express HPV-16 E6 were incubated with compounds, showing dose dependent increase of p53 levels up to 8-fold after 24 hrs, an effect that was not observed in the HPV-16- cell line RPE-1 expressing wild-type p53. Viability of two cervical (SiHa, CaSki) and two oropharyngeal HPV-16+ cancer cell lines (UM-SC-47, UM-SCC-104) was reduced with an IC50 of ~2-3 µM, with an IC50>30µM in RPE-1 cells and telomerase immortalized human keratinocytes. These in vitro and cell-based experiments revealed dependence on the cysteine residue in the E6AP binding pocket of E6. For in vivo proof-of-concept studies, we developed mouse xenograft models, performed by engrafting SiHa, UM-SC-47 and UM-SCC-104 cancer derived cells subcutaneously into the flank of immunodeficient mice. Lead compounds were administered by intraperitoneal injection and demonstrated nearly complete inhibition (> 70% tumor reduction) in HPV-16 tumor growth compared to vehicle. Anti-tumor activity was not observed with the HPV-negative tumor cell line C33A. Conclusions: HPV-16 is identified in about 50% of all cervical cancers and the majority of head and neck malignancies. Inactivation of the HPV E6 protein represents the opportunity for a novel molecular targeted approach for medical treatment of HPV-16 expressing cancers of the cervix and oropharynx.