bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from National Cancer Institute Combination Therapy Platform Trial with Molecular Analysis for Therapy Choice (ComboMATCH)
Authors: Meric-Bernstam Funda , Ford James M. , O'Dwyer Peter J. , Shapiro Geoffrey I. , McShane Lisa M. , Freidlin Boris , O'Cearbhaill Roisin E. , George Suzanne , Glade-Bender Julia , Lyman Gary H. , Tricoli James V. , Patton David , Hamilton Stanley R. , Gray Robert J. , Hawkins Douglas S. , Ramineni Bhanumati , Flaherty Keith T. , Grivas Petros , Yap Timothy A. , Berlin Jordan , Doroshow James H. , Harris Lyndsay N. , Moscow Jeffrey A.
Published: April 2023

Abstract
Over the past decade, multiple trials, including the precision medicine trial National Cancer Institute-Molecular Analysis for Therapy Choice (NCI-MATCH, EAY131, NCT02465060) have sought to determine if treating cancer based on specific genomic alterations is effective, irrespective of the cancer histology. Although many therapies are now approved for the treatment of cancers harboring specific genomic alterations, most patients do not respond to therapies targeting a single alteration. Further, when antitumor responses do occur, they are often not durable due to the development of drug resistance. Therefore, there is a great need to identify rational combination therapies that may be more effective. To address this need, the NCI and National Clinical Trials Network have developed NCI-ComboMATCH, the successor to NCI-MATCH. Like the original trial, NCI-ComboMATCH is a signal-seeking study. The goal of ComboMATCH is to overcome drug resistance to single-agent therapy and/or utilize novel synergies to increase efficacy by developing genomically-directed combination therapies, supported by strong preclinical in vivo evidence. Although NCI-MATCH was mainly comprised of multiple single-arm studies, NCI-ComboMATCH tests combination therapy, evaluating both combination of targeted agents as well as combinations of targeted therapy with chemotherapy. Although NCI-MATCH was histology agnostic with selected tumor exclusions, ComboMATCH has histology-specific and histology-agnostic arms. Although NCI-MATCH consisted of single-arm studies, ComboMATCH utilizes single-arm as well as randomized designs. NCI-MATCH had a separate, parallel Pediatric MATCH trial, whereas ComboMATCH will include children within the same trial. We present rationale, scientific principles, study design, and logistics supporting the ComboMATCH study.
Impact of Biomarker-Matched Therapies on Outcomes in Patients with Sarcoma Enrolled in Early-Phase Clinical Trials (SAMBA 101)
Authors: Carmagnani Pestana Roberto , Moyers Justin T. , Roszik Jason , Sen Shiraj , Hong David S. , Naing Aung , Herzog Cynthia E. , Fu Siqing , Piha-Paul Sarina A. , Rodon Jordi , Yap Timothy A. , Karp Daniel D. , Tsimberidou Apostolia M. , Pant Shubham , Zarzour Maria A. , Ratan Ravin , Ravi Vinod , Benjamin Robert S. , Lazar Alexander J. , Wang Wei-Lien , Daw Najat , Gill Jonathan B. , Harrison Douglas J. , Lewis Valerae O. , Roland Christina L. , Patel Shreyaskumar R. , Livingston J. Andrew , Somaiah Neeta , Ludwig Joseph A. , Conley Anthony P. , Hamerschlak Nelson , Gorlick Richard , Meric-Bernstam Funda , Subbiah Vivek
Published: April 2023

Purpose:

Developing new therapeutics for any of the more than 100 sarcoma subtypes presents a challenge. After progression from standard therapies, patients with sarcoma may be referred for enrollment in early-phase trials. This study aimed to investigate whether enrollment in biomarker-matched early-phase clinical trials leads to better outcomes for patients with advanced sarcoma.

Experimental Design:

In this retrospective analysis, investigational treatment characteristics and longitudinal survival outcomes were analyzed in patients with biopsy-confirmed sarcoma enrolled in early-phase trials at MD Anderson Cancer Center from May 2006 to July 2021.

Results:

Five hundred eighty-seven patients were included [405 soft tissue, 122 bone, 60 gastrointestinal stromal tumor (GIST); median of three prior lines of therapy]. Most common subtypes were leiomyosarcoma (17.2%), liposarcoma (14.0%), and GIST (10.2%). Molecular testing was available for 511 patients (87.1%); 221 patients (37.6%) were treated in matched trials. Overall response rate was 13.1% matched compared with 4.9% in unmatched (P < 0.001); the clinical benefit rate at 6 months was 43.9% vs. 19.9% (P < 0.001). Progression-free survival was longer for patients in matched trials (median, 5.5 vs. 2.4 months; P < 0.001), and overall survival was also superior for patients in matched trials (median, 21.5 vs. 12.3 months; P < 0.001). The benefit of enrollment in matched trials was maintained when patients with GIST were excluded from the analysis.

Conclusions:

Enrollment in biomarker-matched early-phase trials is associated with improved outcomes in heavily pretreated patients with metastatic sarcoma. Molecular testing of tumors from patients with advanced sarcoma and enrollment in matched trials is a reasonable therapeutic strategy.
Combination Treatment with Sipuleucel-T and Abiraterone Acetate or Enzalutamide for Metastatic Castration-Resistant Prostate Cancer: STAMP and STRIDE Trials
Authors: Antonarakis Emmanuel S. , Subudhi Sumit K. , Pieczonka Christopher M. , Karsh Lawrence I. , Quinn David I. , Hafron Jason M. , Wilfehrt Helen M. , Harmon Matthew , Sheikh Nadeem A. , Shore Neal D. , Petrylak Daniel P.
Published: April 2023

Purpose:

We present long-term outcomes from 2 randomized studies [STAMP (with abiraterone, NCT01487863) and STRIDE (with enzalutamide, NCT01981122)] that were performed to study the impact of sequential or concurrent administration of androgen receptor–targeting agents (ARTAs) on sipuleucel-T immune response and overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC).

Patients and Methods:

Sipuleucel-T was administered per current prescribing information. Results from STRIDE are presented together with updated STAMP results. Survival status of patients was updated using demographic information to query the National Death Index (NDI). Kaplan–Meier methodology was used to analyze survival.

Results:

Updated data reduced patient censoring in each study compared with the original analyses; the 95% confidence intervals (CIs) for OS are now estimable. Updated median OS (95% CI) is 33.3 (24.1–40.7) months for STAMP and 32.5 (26.0–45.1) months for STRIDE. There was no notable impact on median OS [HR, 0.727 (0.458–1.155); P = 0.177, reference = STRIDE]. OS with sequential administration was similar to concurrent administration [NDI update: HR, 0.963 (0.639–1.453); P = 0.845, reference = concurrent arm]. Sipuleucel-T potency, measured as antigen-presenting cell (APC) activation, was higher in subsequent infusions compared with the first infusion. Humoral responses (IgG + IgM antibody titers) to PA2024 and prostatic acid phosphatase were significantly elevated versus baseline. No new safety signals were observed.

Conclusions:

Median OS was consistent regardless of whether the agents were administered sequentially or concurrently, including after NDI update. Results suggest that sipuleucel-T induces an immunologic prime-boost effect after initial sipuleucel-T exposure, even when combined with ARTAs.
Abstract CT135: A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors
Authors: Bacha Jeffrey , Brown Dennis , Kanekal Sarath , Sankar Neil , Lopez Lorena , Yam Noymi , Wagner Lars , Geller James , Leggas Markos , Thompson Patrick , Osterheld Javier
Published: April 2023

Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan.

Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled.

Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented.

Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated.

Outcome Measures: Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intrapatient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date.

Citation Format: Jeffrey Bacha, Dennis Brown, Sarath Kanekal, Neil Sankar, Lorena Lopez, Noymi Yam, Lars Wagner, James Geller, Markos Leggas, Patrick Thompson, Javier Osterheld. A pilot clinical study of orotecan (oral irinotecan HCl, VAL-413) in patients with recurrent pediatric solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT135.
Abstract LB013: Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma survival
Authors: Agrawal Praveen
Published: April 2023

Glycosylation is a hallmark of cancer biology, and altered glycosylation influences multiple facets of melanoma growth and progression. To identify glycosyltransferases, glycans, and glycoproteins essential for melanoma survival, we conducted an in vivo growth screen with a pooled shRNA library of glycosyltransferases, lectin microarray profiling of benign nevi and melanoma patient samples, and mass spectrometry-based glycoproteomics. We found that alpha-2,3 sialyltransferases ST3GAL1 and ST3GAL2 and corresponding alpha-2,3-linked sialosides are upregulated in melanoma compared to nevi and are essential for melanoma growth in vivo and in vitro. Glycoproteomics revealed that glycoprotein targets of ST3GAL1 and ST3GAL2 are enriched in transmembrane proteins involved in growth signaling, including the amino acid transporter Solute Carrier Family 3 Member 2 (SLC3A2/CD98hc). CD98hc suppression mimicked the effect of ST3GAL1 and ST3GAL2 silencing, inhibiting melanoma cell proliferation. We found that both CD98hc protein stability and its pro-survival effect in melanoma are dependent upon alpha–2,3 sialylation mediated by ST3GAL1 and ST3GAL2. In summary, our studies reveal that alpha-2,3-sialosides functionally contribute to melanoma maintenance, supporting ST3GAL1 and ST3GAL2 as novel therapeutic targets in these tumors.

Citation Format: Praveen Agrawal. Integrated in vivo functional screens and multi-omics analyses identify alpha-2,3-sialylation as essential for melanoma survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB013.
Abstract LB037: Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene
Authors: Chen Jilong , Ma Yun
Published: April 2023

Chronic myeloid leukemia (CML) is a hematological malignancy mainly caused by the Bcr-Abl oncogene that results from the reciprocal translocation between human chromosome 9 and 22, and occurs in more than 90% of CML cases. Bcr-Abl oncogene is also involved in tumorigenesis of other leukemia such as acute lymphoid leukemia (ALL). Although progress has been made in the understanding of signal transduction in Abl-mediated transformation, the molecular mechanisms underlying Abl-induced tumorigenesis are still not fully understood. It is well known that imatinib treatment can greatly suppress Bcr-Abl-mediated development of leukemia, but intracellular molecules induced by imatinib and their roles in the tumorigenesis remain largely to be determined. On the other hand, the majority of human transcripts lack protein-coding capacity, which are defined as noncoding RNAs (ncRNAs). Long noncoding RNAs (lncRNAs) play important roles in various vital biological processes. Notably, increasing number of lncRNAs have been linked to human diseases, including cancers. However, the role of lncRNAs in Bcr-Abl-induced leukemia remains largely unexplored. Here, we identified several imatinib-induced lncRNAs as critical regulator of Bcr-Abl-induced tumorigenesis. Most of these lncRNAs expressed in a very low levels in Bcr-Abl-positive cells from chronic myeloid leukemia patients. Interestingly, they could be significantly induced in Abl-positive leukemic cells treated by imatinib. Silencing these lncRNAs promoted survival of Abl-transformed human leukemic cells in experiments in vitro and xenografted tumor growth in mice, whereas ectopic expression of particular lncRNAs sensitized the cells to apoptosis and suppressed tumor growth. In concert, knockout of some murine lncRNAs in Abl-transformed cells accelerated cell survival and the development of leukemia in mice. Furthermore, some lncRNA deficient mice were generated, and we observed that knockout of particular murine lncRNAs facilitated Bcr-Abl-mediated primary bone marrow transformation. Moreover, animal leukemia model revealed that lncRNA deficiency promoted Abl-transformed cell survival and development of leukemia in mice. In summary, these findings unveil an inhibitory role of several critical lncRNAs in Abl-mediated cellular transformation, and provide new insights into molecular mechanisms underlying Abl-induced leukemogenesis.

Citation Format: Jilong Chen, Yun Ma. Identification of imatinib-induced long noncoding RNAs involved in suppression of tumor growth mediated by bcr-abl oncogene [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB037.
Abstract LB044: Modeling the role of ARID1A in colon cancer using patient-derived organoids
Authors: Deary Luke T. , Sugiarto Nicholas , Pigeon Cameron , Mayo Sara W. , Wilson Matthew Z. , Wang Xiaofeng
Published: April 2023

Loss-of-function (LOF) mutations in genes encoding subunits of SWI/SNF chromatin remodeling complexes are found in approximately 25% of human cancers. Colorectal cancers (CRC), the second leading cause of cancer related deaths, are particularly vulnerable to SWI/SNF driver mutations, harboring subunit alterations in up to 55% of patient tumors. ARID1A, a BAF subcomplex specific subunit, is the most frequently mutated subunit in human cancers (12%) and CRCs (10-12%). Additionally, ARID1A was recently identified as a leading genetic alteration in inflammatory bowel diseases such as Crohn’s and Ulcerative Colitis, conditions which are at higher risk of developing CRC. These data suggest an important role in ARID1A regulation of colonic tissue homeostasis and the potential for ARID1A mutation as an initiating or early driving event in CRC, which has not yet been modeled in human colon tissues. To examine the role of ARID1A in colon cancer development, we took a bottom-up strategy using CRISPR edited patient-derived colon organoids to model ARID1A LOF mutations in combination with classic CRC mutations APC and TP53. We evaluated the functional consequences of ARID1A mutation on cell growth using colony formation and proliferation assays. To systematically investigate the phenotypic contribution of ARID1A loss in these cell contexts, we employed transcriptomic and epigenomic profiling with RNAseq and ATACseq. We found that triple knock-out (TKO) of ARID1A, APC and TP53 confers a growth advantage in colon organoids, and induces dramatic morphological changes such as loss of symmetry and the breakdown of cystic architectures. At the gene expression level, ARID1A mutations led to shared and cell context specific transcriptional changes enriched for pathways such as G2M checkpoint, KRAS Signaling, and STAT5 signaling. Mechanistically, we show that ARID1A dependent chromatin accessibility changes at putative enhancers are linked to promoters of differentially expressed genes. These data suggest that ARID1A can regulate multiple cancer hallmark pathways depending on the cellular context and indicate a pleiotropic tumor suppressive function requiring further investigation in clinically relevant genetic backgrounds.

Citation Format: Luke T. Deary, Nicholas Sugiarto, Cameron Pigeon, Sara W. Mayo, Matthew Z. Wilson, Xiaofeng Wang. Modeling the role of ARID1A in colon cancer using patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB044.
Abstract LB059: DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer
Authors: Zhivagui Maria , Hoda Areebah , Valenzuela Noelia , Yeh Yi-yu , Dai Jason , He Yudou , Nandi Shuvro P. , Otlu Burcak , Van Houten Bennett , Alexandrov Ludmil
Published: April 2023

Ultraviolet A (UVA) rays are long wavelengths that can penetrate the deeper layer of the skin and are responsible for the immediate tanning effect. A multitude of natural and artificial sources of UV exposure exist, including UV-emitting lamps that are commonly used in dentistry, cosmetics, and medical laboratories. Recently, several reports suggested that long-term use of UV-nail polish dryers, used for curating nail polish formulas, known as gel, may increase the risk for developing skin cancer. However, no experimental evaluation has been conducted to reveal the effect of radiation released by UV-nail polish dryers on mammalian cells. Here, we address the continuous exposure of clients and employees to UVA light by employing both murine and human primary cell models for irradiation, in an acute and chronic manner, using a UV-dryer machine. We, then, subject the cells to DNA sequencing either by bulk whole-genome sequencing after clonal expansion or by single-molecule duplex sequencing without clonal expansion. Our findings show that UVA-exposed samples manifest an increase of C:G>A:T transversions compared to control cells. The patterns of mutations found in these cells can be recapitulated by mutational signatures previously attributed to reactive oxygen species (ROS), namely COSMIC signatures SBS18/36. These results are further corroborated by the presence of high levels of ROS in irradiated samples, consistent with 8-oxo-7,8-dihydroguanine damage and mitochondrial dysfunction. Importantly, we show that in contrast to UVB exposure, UVA does not induce an increase of C:G>T:A transitions, indicating that different types of ultraviolet light radiation affect DNA through distinctive molecular mechanisms. Finally, re-examination of somatic mutations from skin cancers reported by the International Cancer Genome Consortium (ICGC) reveals that SBS18/36 are ubiquitously present in melanoma and account for 12% of the previously annotated driver mutations. In summary, this study demonstrates that radiation emitted by UV-nail polish dryers can both damage DNA and permanently engrave mutations on the genomes of mammalian cells.

Citation Format: Maria Zhivagui, Areebah Hoda, Noelia Valenzuela, Yi-yu Yeh, Jason Dai, Yudou He, Shuvro P. Nandi, Burcak Otlu, Bennett Van Houten, Ludmil Alexandrov. DNA damage and somatic mutations in mammalian cells after irradiation with a nail polish dryer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB059.
Abstract LB082: The CytoR1: a standardized dielectrophoretic platform for label free sorting
Authors: Thomas Dean E. , Degen Katherine E. , Barua Ridi , Bertke Andrea , Henslee Erin A. , Hyler Alexandra R.
Published: April 2023

Dielectrophoresis (DEP), a label-free electrokinetic technique, has a long history of being used to characterize and separate target subpopulations from mixed samples. A large body of literature has investigated these parameters with unique setups and limited cell varieties. The technical challenge of the technique coupled with the uncertainty in the breadth of data has limited the commercialization and widespread adoption of DEP for biological applications. The work presented here aims to evaluate a range of prior applications of DEP on a standardized platform. A variety of cell types were characterized and compared to literature values considering variables such as frequency, voltage, and flow rate. Once a cell type’s frequency response curve is generated, it is possible to design workflows to enrich that cell type from a bulk mixture, without antibody labeling. Here, we test various cell types and characteristics on a microfluidics-based, benchtop cell sorting technology, the CytoR1. First, the CytoR1 successfully facilitated the separation of ovarian cancer stem cells (CSCs) from peripheral blood mononuclear cells (PBMCs), both from mice. From a 56.2% CSCs and 43.8% PMBCs co-culture, we were able to deplete 50% of the PMBCs while retaining the original CSC population. Further work investigated the ability to sort neuron subpopulations. Live neurons can be isolated from a bulk preparation and further enriched by size and phenotype with varying voltage and frequency settings. By modulating voltage and flow rate in addition to frequency, a distinct population of small neurons can be isolated for further study. Finally, cell state can be investigated. Red blood cells were characterized in both their native and oxidatively stressed states. Curves show a distinct shift towards higher frequencies with increasing oxidative stress suggesting the ability to separate these populations from each other. Together these data suggest the versatility of a robust, DEP-based sorting platform, the CytoR1, for label free cell sorting.

Citation Format: Dean E. Thomas, Katherine E. Degen, Ridi Barua, Andrea Bertke, Erin A. Henslee, Alexandra R. Hyler. The CytoR1: a standardized dielectrophoretic platform for label free sorting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB082.
Abstract LB098: Combination of a PD-1/CTLA-4 bispecific antibody with orally active PD-L1 inhibitor MAX-10181 effectively increased the percentage of tumors inhibited in animal model study
Authors: Wang Yuguang , Gao Yuan , Mao Chenyu , Xu Nong , Zhang Qiang , Wang Jing , Feng Zhenhua , Zhu Yonghong , Wang Zhongmin , Li Baiyong
Published: April 2023

The key players in the current immuno checkpoint inhibition (ICI) treatment are antibodies or bispecific antibodies targeting PD-1. PD-L1 or CTLA-4. While these drugs provided a small number of patients with tumor shrinking (ORR between 10-30%) as a single agent, they did not lead to desirable treatment survival as measured by OS/PFS. Many combination studies are in progress in both preclinical and clinical settings to find an effective way to achieve prolonged OS/PFS in ICI treatment. Herein, we would like to report our most recent findings of combination of a PD-1/CTLA-4 bispecific antibody with our orally active, clinical stage PD-L1 inhibitor MAX-10181 in animal model study. The key observations are as follow:

•The PD-1/CTLA-4 bispecific antibody group (n=10, average starting tumor volume= 68 mm3) demonstrated (a) 2 tumors (20%) in the slow volume shrinking mode with volume between 60-20 mm3, and (b) 4 tumors (40%) in the fast volume growing mode with volume above 500 mm3

•The combination group (n=10, average starting tumor volume= 68 mm3) demonstrated (a) 2 tumors (20%) in the fast volume shrinking mode with volume less than 20 mm3, (b) 1 tumor (10%) in the slow volume shrinking mode with volume between 60-20 mm3, and (c) only 1 tumor (10%) in the fast volume growing mode with volume above 500 mm3

These results indicate the potential of prolonged OS/PFS to combine PD-1/CTLA-4 bispecific antibody with orally active, small molecule MAX-10181 which recently completed Phase I trial. We will present the full study results in the coming AACR meeting.

Citation Format: Yuguang Wang, Yuan Gao, Chenyu Mao, Nong Xu, Qiang Zhang, Jing Wang, Zhenhua Feng, Yonghong Zhu, Zhongmin Wang, Baiyong Li. Combination of a PD-1/CTLA-4 bispecific antibody with orally active PD-L1 inhibitor MAX-10181 effectively increased the percentage of tumors inhibited in animal model study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB098.
Abstract LB099: Organoid-based drug efficacy evaluation model for immunotherapy
Authors: Lee Boeun , Yang Woo Kyeom , Kim Sarang , Lee Hee-Ra , Kim Donghyeon , Yoo Jongman
Published: April 2023

The endogenous immune system of patients are known to be activated through immuno-oncology drug, which activates the patient’s own immune system to target and attack tumors. Due to the relatively low occurrence of side effects and sustained success, these therapeutic techniques have gradually replaced the traditional cancer treatment regimen. The creation of an in-vitro screening platform for pre-evaluating the efficacy of immunotherapeutic drug candidates was highly essential despite the fact that many of the new emerging therapies had failed clinical trials.An in-vitro platform mirroring the interaction between a patient's unique Major Histocompatibility Complex (MHC) and T-cell receptor (TCR) is necessary for predicting the precise efficacy of immunotherapies. The tumor cells' MHC antigen molecule attaches to the T-cell receptor (TCR), allowing T-cells to manifest their tumor-killing activities as a result. The link between immunological checkpoint (ICP) in tumor cells and their receptors in T cells allows tumor cells to evade the effects of T-cell-mediated tumor death.We would like to introduce our "ODISEI" platform, a robust efficacy evaluation tool that enables the recapitulation of a patient's unique immune system, utilizing tumor organoids and PBMC from the same donors. Using PD-1/PD-L1 inhibiting antibodies, the enhanced functionality of our ODISEI platform as an effective evaluation platform for immunotherapy drugs was thoroughly examined. Additionally, we created several ODISEI platforms in order to recreate the precise interactions between tumor organoids and various immune sub-populations (T-cells, macrophages, regulatory T-cells, and dendritic cells). Our ODISEI platforms were validated by utilizing a variety of different drug candidates and evaluating their ability to eradicate tumors upon interaction with various reactive immune cells and tumors. As a result, our highly innovative ODISEI platform can be used to screen a variety of different immunotherapeutic drug candidates and distinguish their precise efficacy.

Citation Format: Boeun Lee, Woo Kyeom Yang, Sarang Kim, Hee-Ra Lee, Donghyeon Kim, Jongman Yoo. Organoid-based drug efficacy evaluation model for immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB099.
Abstract LB137: Ovulatory years prior to menopause and postmenopausal endogenous hormone levels
Authors: Cramer Daniel W. , Vitonis Allison F. , Huang Tianyi , Shafrir Amy L. , Eliassen Heather , Barbieri Robert L. , Hankinson Susan E.
Published: April 2023

Background: Estimated lifetime ovulatory years (LOY) is the difference between ages at menopause and menarche subtracting time for events interrupting ovulation. We tested whether LOY influence sex-hormone levels in postmenopausal women not using hormone therapy.

Methods: Hormones, including estradiol and testosterone, were measured in 1976 postmenopausal women from the Nurses’ Health Study in plasma collected in 1990. Effects of age, years since menopause, body mass index (BMI), smoking status, and hysterectomy on hormone levels were assessed by t-tests and ANOVA. Multivariable linear regression was used to assess associations between LOY and hormones adjusted for potential confounders and the trend in hormone levels per 5-year increases in LOY estimated.

Results: Women in the sample averaged: 61.4 years old at blood draw, 11.0 years since menopause, with a BMI of 25.8 kg/m2. 17.5% had a hysterectomy and 13.8% were current smokers. These characteristics were associated with one or more hormone levels and included as adjustment variables. Each 5-year increase in LOY was associated with a 6.0% increase in testosterone (95% CI 3.3%, 8.7%) in all women. In women with above-average BMI, each 5-year increase in LOY was associated with a 7.3% (3.5%, 11.2%) increase in testosterone, a 6.9% (2.7%,11.3%) increase in estradiol, and a 6.9% (2.9%,10.9%) increase in estrone.

Conclusion: Greater LOY is associated with higher testosterone in postmenopausal women as well as greater estradiol in those with above-average BMI. This may be due to an accumulation of functioning stromal and thecal cells from repeated ovulation and peripheral conversion of testosterone.

Citation Format: Daniel W. Cramer, Allison F. Vitonis, Tianyi Huang, Amy L. Shafrir, Heather Eliassen, Robert L. Barbieri, Susan E. Hankinson. Ovulatory years prior to menopause and postmenopausal endogenous hormone levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB137.
Abstract LB168: Efficacy analysis of the DeepNeo neoantigen prediction tool for antitumor vaccine development
Authors: Lee Eun Ji , Park Min Ji , Kim Soo Jin , Noh Seung-Jae , Shin Inkyung , Kim Jeong Yeon , Shin Incheol , Choi Jung Kyoon , Cho Dae-Yeon , Chang Suhwan
Published: April 2023

Antitumor peptide vaccine is an alternative and attractive way to eradicate tumors by the aid of host immune system. The current peptide vaccine development is hampered by several hurdles. These include heterogeneity of tumor cells, applicable in vivo stability of peptides, and others. One of the major obstacles is the precise prediction of cancer antigen, which can be loaded efficiently onto antigen presenting cells. We present here a neoantigen prediction algorithm DeepNeo comprised of DeepNeo-MHC and DeepNeo-TCR, which calculates the antigenicity of neoantigen based on the MHC binding and TCR activation potential. We examined the efficacy of DeepNeo using ELISPOT and two allogenic mouse tumor models. By treating the combination of long peptides targeting MC38 colon or B16F10 melanoma cell lines, we have shown the DeepNeo effectively determines neoantigens for the development of antitumor peptide vaccine. Analysis of tumor-infiltrated lymphocytes (TIL) supported our results. Undergoing study using patient-derived xenograft model treated with autologous, trained PBMC with personalized peptide vaccine will be discussed further.

Citation Format: Eun Ji Lee, Min Ji Park, Soo Jin Kim, Seung-Jae Noh, Inkyung Shin, Jeong Yeon Kim, Incheol Shin, Jung Kyoon Choi, Dae-Yeon Cho, Suhwan Chang. Efficacy analysis of the DeepNeo neoantigen prediction tool for antitumor vaccine development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB168.
Abstract LB171: WSI based prediction of TP53 mutations identifies aggressive disease phenotype in prostate cancer
Authors: Pizurica Marija , Larmuseau Maarten , Van der Eecken Kim , de Schaetzen van Brienen Louise , Carrillo-Perez Francisco , Isphording Simon , Lumen Nicolaas , Van Dorpe Jo , Ost Piet , Verbeke Sofie , Gevaert Olivier , Marchal Kathleen
Published: April 2023

In prostate cancer, there is an urgent need for objective prognostic biomarkers that identify a tumor’s metastatic potential at an early stage. While recent analyses indicated TP53 mutations as candidate biomarker, molecular profiling in a clinical setting is complicated by tumor heterogeneity. Deep learning models that predict the spatial presence of TP53 mutations in Whole Slide Images (WSIs) offer the potential to mitigate this issue. To assess the potential of WSIs as proxy for spatially resolved profiling or as biomarker for aggressive disease, we developed TiDo, a deep learning model that achieves state-of-the-art performance in predicting TP53 mutations from WSIs of primary prostate tumors. On an independent multi-focal cohort, we could show successful generalization of the model, both at patient and lesion level. Hence, the model offers insight into which lesions on a WSI most likely contain a TP53 mutation.

Analysis of model predictions revealed that false positive (FP) predictions could at least partially be explained by TP53 deletions. This suggests that some FP carry another alteration of which the effect converges in the same histological phenotype. Comparative expression analysis and histological cell type analysis identified such common phenotype (related to stromal composition) in both TP and FP predictions. This indicates that WSI-based models might not be able to perfectly predict the spatial presence of individual TP53 mutations. However, we show they have the potential of capturing a tumor’s aggressive potential by observing a downstream phenotype of the tumor cells and TME associated with a biomarker of aggressive disease (TP53).

Citation Format: Marija Pizurica, Maarten Larmuseau, Kim Van der Eecken, Louise de Schaetzen van Brienen, Francisco Carrillo-Perez, Simon Isphording, Nicolaas Lumen, Jo Van Dorpe, Piet Ost, Sofie Verbeke, Olivier Gevaert, Kathleen Marchal. WSI based prediction of TP53 mutations identifies aggressive disease phenotype in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB171.
Abstract LB174: Diabetes-associated breast cancer is molecularly distinct and shows DNA repair deficiency
Authors: Panigrahi Gatikrushna , Candia Julián , Dorsey Tiffany H. , Tang Wei , Ohara Yuuki , Byun Jung S. , Minas Tsion Zewdu , Zhang Amy , Ajao Anuoluwapo , Cellini Ashley , Yfantis Harris G. , Mann Dean , Ioffe Olga , Wang Xin W. , Liu Huaitian , Loffredo Christopher A. , Napoles Ana Maria , Ambs Stefan
Published: April 2023

Diabetes commonly affects cancer patients. In breast cancer, it decreases patient survival. Diabetes also impacts African American women more so than European American women, potentially contributing to the breast cancer health disparity. In this study, we investigated the influence of diabetes on breast cancer biology in a diverse patient cohort using a three-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes does not enhance cell proliferation but induces mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. It also promotes oxyradical formation and both transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tend to accumulate in breast tumors in presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquire increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors that are cancer therapeutics.

Key words: Breast cancer, diabetes, metabolome, transcriptome, metastasis, DNA repair, mutational signature, health disparity

Citation Format: Gatikrushna Panigrahi, Julián Candia, Tiffany H. Dorsey, Wei Tang, Yuuki Ohara, Jung S. Byun, Tsion Zewdu Minas, Amy Zhang, Anuoluwapo Ajao, Ashley Cellini, Harris G. Yfantis, Dean Mann, Olga Ioffe, Xin W. Wang, Huaitian Liu, Christopher A. Loffredo, Ana Maria Napoles, Stefan Ambs. Diabetes-associated breast cancer is molecularly distinct and shows DNA repair deficiency [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB174.
Abstract LB178: Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA
Authors: Moore Travis , Spiliotopolous Elias , Callahan Rowan , Kirschbaum Ward , Kim Hyun Ji , Keith Dove , Grossberg Aaron , Spellman Paul T. , Mills Gordon , Sears Rosalie C. , Morgan Terry , Ngo Thuy
Published: April 2023

Endoscopic ultrasound (EUS), the primary procedure for the diagnosis of pancreatic ductal adenocarcinoma (PDAC), the most lethal cancer, is invasive. We aim to develop a liquid biopsy approach using plasma cell-free messenger RNA to stratify patients prior to EUS and assist in the precision diagnosis of PDAC. We found a set of plasma cell-free messenger RNA biomarkers and a set of robust reference genes to classify PDAC patients from intermediary pancreatic pathologies such as: benign cases, pancreatitis, and intraductal papillary mucinous neoplasm (IPMN) with reproducible results validated in separate cohorts. Our results demonstrate a non-invasive liquid biopsy approach for stratifying patient groups before invasive and definitive EUS screening.

Citation Format: Travis Moore, Elias Spiliotopolous, Rowan Callahan, Ward Kirschbaum, Hyun Ji Kim, Dove Keith, Aaron Grossberg, Paul T. Spellman, Gordon Mills, Rosalie C. Sears, Terry Morgan, Thuy Ngo. Cell free RNA for prediction of PDAC in de novo symptomatic patients presenting for EUS-FNA [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB178.
Abstract LB212: BCG022: A novel bispecific antibody-drug conjugate targeting HER3 and MET
Authors: Li Zhuolin , Shang Chengzhang , Guan Xuewa , Han Zhenyan , An Gao , Zhang Ellen , Lin Qingcong , Yang Yi
Published: April 2023

HER3 is a unique EGFR family member that plays a role in both tumor progression and drug resistance. Its expression can act as a bypass mechanism for EGFR and HER2-targeted therapies, resulting in therapeutic resistance. MET has also been reported as a bypass resistance mechanism to EGFR-TKI treatment. HER3 and MET are co-expressed at high prevalence in multiple tumor types, including gastric, colorectal, breast, and non-small-cell lung cancer (NSCLC). In addition, HER3 and MET are frequently overexpressed in liver metastases from patients with colorectal cancer, indicating that targeting both proteins may provide clinical benefit. We generated fully human bispecific antibodies (bsAbs) targeting HER3 and MET with cross-species reactivity, using RenLite® mice, which contain the full human heavy chain variable domain with a common human kappa light chain to facilitate future bispecific antibody assembly. These 1+1 bsAbs have demonstrated enhanced internalization compared to the parental monoclonal antibodies in multiple cancer cell lines. These bsAbs were then conjugated with Monomethyl auristatin E (MMAE) to generate HER3 and MET-targeting bispecific ADC (BCG022) candidates. In vivo drug efficacies are being screened using cell-derived hepatocellular carcinoma (HCC) and gastric carcinoma xenografts, as well as patient-derived gastric and pancreatic xenograft models. Collectively, these results suggest that BCG022 has the potential to be a novel therapeutic option for HER3 and MET co-expressing tumors.

Citation Format: Zhuolin Li, Chengzhang Shang, Xuewa Guan, Zhenyan Han, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. BCG022: A novel bispecific antibody-drug conjugate targeting HER3 and MET [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB212.
Abstract LB214: A first-in-class bispecific antibody-drug conjugate (DM002) targeting HER3 and the juxtamembrane domain of MUC1
Authors: Zhang Yifu , Shang Chenzhang , Wang Nannan , An Gao , Zhang Ellen , Lin Qingcong , Yang Yi
Published: April 2023

Despite the entry of new anti-cancer drugs into the market, there were more than 10 million deaths from cancer globally in 2021, with cancers of the lung, stomach, breast, and pancreas contributing to the most cancer-related deaths in China and the USA. Accordingly, there is an urgent need for improved therapeutic interventions. Antibody-drug conjugates (ADC) are novel drugs that exploit the specificity of a monoclonal antibody for target antigens expressed on cancer cells in order to achieve targeted delivery of a potent cytotoxic payload. More recently, bispecific ADCs (BsADC) targeting two tumor-associated antigens (TAA) have been developed to further amplify tumor cell specificity while minimizing toxicity to normal tissue, thus allowing for broader therapeutic windows. HER3 and MUC1 are two TAAs that are commonly expressed/co-expressed on multiple tumor types, including lung, gastric, breast and pancreatic cancer; however, neither antigen has been successfully targeted by effective drugs: of the candidates targeting HER3 antigen being evaluated in human clinical studies, most are well-tolerated, but with limited efficacy. On the other hand, high levels of MUC1 in diseased tissues can undergo auto-proteolysis, so that drugs targeting the MUC1-N region will be neutralized before reaching the tumor tissues, thereby limiting the recognition of tumor cells. To overcome these challenges, we generated fully human bispecific antibody candidates with human-monkey cross-species reactivity that target HER3 and the juxtamembrane domain of MUC1. These bsAbs exhibit higher endocytic activity in HER3-low tumor cell lines compared with other currently available HER3 mAb. These bsAbs were subsequently conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker to obtain first-in-class BsADC candidates, DM002. DM002 candidates showed robust anti-tumor activity in multiple CDX and PDX models of lung, breast, gastric and pancreatic cancer; most notably, DM002 candidates outperformed benchmark ADCs in BP0508 lung PDX models. Together, these data indicate that DM002 will be a promising therapeutic drug for patients with HER3 and MUC1 co-expressing tumors.

Citation Format: Yifu Zhang, Chenzhang Shang, Nannan Wang, Gao An, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class bispecific antibody-drug conjugate (DM002) targeting HER3 and the juxtamembrane domain of MUC1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB214.
Abstract LB233: Preclinical analysis identifies predictive biomarker and potential pathways of resistance to lurbinectedin treatment in small cell lung cancer
Authors: Chakraborty Subhamoy , Coleman Charles , Demircioglu Deniz , Hasson Dan , Sen Triparna
Published: April 2023

Background: Small cell lung cancer (SCLC) is an exceptionally aggressive disease with limited treatment options that typically result in transient responses. SCLC is responsible for approximately 250,000 deaths globally per year. Major hurdles to improving SCLC treatment include the development of rapid chemo-resistance and limited second-line therapies. Lurbinectedin is FDA approved as a second-line treatment for SCLC but shows a response in a subset of patients. Therefore, improved mechanistic understanding and identifying predictive biomarkers of lurbinectedin treatment is a major unmet clinical need.

Methods: We treated SCLC cell lines and patient-derived xenograft (PDX) models from all major SCLC subtypes with lurbinectedin. Lurbinectedin-mediated changes in signaling pathways were studied by bulk RNA sequencing, western blot, and flow cytometry. Anti-tumor efficacy and toxicity studies were performed in vivo.

Result: All human and PDX-derived SCLC cell lines showed sensitivity to lurbinectedin at a nano-molar concentration ranging from 1.905 to 30 nM. Bulk RNA-seq analysis showed lurbinectedin induced changes in neuroendocrine phenotype, DNA damage response and tumor progression markers in vitro. Single agent treatment of lurbinectedin showed remarkable anti-tumor efficacy in an ASCL1-driven PDX model. RNA sequencing analysis identified modulation of genes in multiple signaling pathways including PI3K-AKT, apoptosis and EMT to be significantly associated with the lurbinectedin response in PDX models.

Conclusion: There is an immediate need to understand the subsets of SCLC that would be most sensitive to lurbinectedin and identify predictive biomarkers. We demonstrate MYC as a predictive biomarker for lurbinectedin response. We are the first to show that single agent lurbinectedin shows remarkable anti-tumor efficacy in a ASCL1-driven PDX models of SCLC. Furthermore, our pre and post-lurbinectedin treatment transcriptomic analysis identify the pathways that may contribute to primary or acquired resistance to lurbinectedin in SCLC. Finally, we identity candidate targets that would guide the design of future combination clinical trials with lurbinectedin in SCLC.

Citation Format: Subhamoy Chakraborty, Charles Coleman, Deniz Demircioglu, Dan Hasson, Triparna Sen. Preclinical analysis identifies predictive biomarker and potential pathways of resistance to lurbinectedin treatment in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB233.