bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1620: Identification of a molecular degrader targeting the AR-V7 splice variant
Authors: Liu Yuan , Lin Bo , Larsen Mads B. , Alfaras Irene , Kennerdell Jason R. , Camarco Daniel P. , Tuncer Ferhan , Finkel Toren , Chen Bill B.
Published: April 2023

Prostate cancer is the most common cancer in males and the fifth leading cause of cancer mortality worldwide. A variety of therapeutic approaches exist including steroid synthesis inhibitors and next-generation ligand binding domain (LBD) antagonists [e.g., enzalutamide (Enza)]. However, these approaches are only effective against tumors bearing the full-length androgen receptor (AR-FL). In the course of their disease, many patients acquire androgen receptor splice variant 7 (AR-V7), a mutant form of the receptor which lacks the LBD and is constitutively activated. To date, no effective therapy has been demonstrated for patients with metastatic prostate cancer bearing the AR-V7 signature. We have recently developed a high throughput platform that allows for the identification of ligands that can bind to wide variety of protein targets. Using this approach, we screened a diverse chemical library of 100,000 small molecules to identify compounds that bound to AR-V7. One such molecule, CL-AR-100, directly bound to AR-V7 and moreover, induced proteasomal-mediated targeted protein degradation of both AR-V7 and AR-FL. This compound did not affect the expression of other structurally related ligand-activated nuclear receptors. In prostate cancer cell lines expressing AR-FL, CL-AR-100 induced a gene expression profile similar to cells treated with Enza including a marked reduction in KLK3 (PSA) expression. Moreover, CL-AR-200 inhibited the growth of 22RV1 cells (IC50=0.3uM), a cell line that predominantly expresses AR-V7. In contrast, the compound did not affect the growth of a wide variety of non-tumorigenic cells, non-prostate tumor cell lines or PC3 cells, a prostate cell line that exhibits AR-independent cell growth. These results thereby identify a small molecule molecular degrader that can specifically induce the targeted protein degradation of the AR-V7 splice variant. Given the strong association of this isoform with treatment resistance, this approach would appear to provide an attractive strategy for patients with metastatic castration resistant prostate cancer.

Citation Format: Yuan Liu, Bo Lin, Mads B. Larsen, Irene Alfaras, Jason R. Kennerdell, Daniel P. Camarco, Ferhan Tuncer, Toren Finkel, Bill B. Chen. Identification of a molecular degrader targeting the AR-V7 splice variant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1620.
Abstract 1645: JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division
Authors: Yang Guiqun , Wang Yanping , Li Haijun , Chen Mingming , Lin Yiwei , Sun Xin
Published: April 2023

Background: Aurora kinase A (AURKA), a crucial mitotic regulator, is frequently dysregulated in a wide range of cancers and contributes to clinical aggressiveness and poor patient survival. Abnormally activated AURKA promotes tumorigenesis through enhancing cancer cell proliferation, epithelial-mesenchymal transition, and cancer stem cell self-renewal, rendering it an attractive therapeutic target. We have developed JAB-2485, a highly selective small-molecule AURKA inhibitor.

Methods: Biochemical and cell-based assays were performed to determine the IC50 of JAB-2485 on Aurora kinase family members. Fluorescence activated cell sorting (FACS) and caspase 3/7 assay were performed to detect JAB-2485-induced cell cycle arrest and apoptosis, respectively. The CellTiter-Glo assay was performed to evaluate the effect of JAB-2485 in multiple cancer cell lines. Finally, the antitumor effect of JAB-2485 either as a single agent or in combinations was investigated in tumor cell line-derived xenografts.

Results: JAB-2485 is potent and highly selective on AURKA, with IC50 of 0.33nM and around 1700-fold selectivity over AURKB. Following treatment of JAB-2485, the level of AURKA phosphorylation as a pharmacodynamic marker was significantly decreased in a dose-dependent manner. As a single agent, JAB-2485 inhibited in vitro proliferation of small cell lung cancer (SCLC), triple-negative breast cancer (TNBC) and neuroblastoma cell lines along with induced G2/M cell cycle arrest and apoptosis, and significantly inhibited in vivo tumor growth on SCLC and neuroblastoma xenografts. Furthermore, JAB-2485 showed strong synergy with cisplatin and paclitaxel in SCLC and TNBC animal models, respectively.

Conclusions: Taken together, preclinical results provide robust evidence supporting further evaluation of JAB-2485 both as a single agent and in combinations for treatment of various types of cancers. A Phase 1/2a clinical trial of evaluating JAB-2485 in adult patients with advanced solid tumors is enrolling patients in the US (NCT05490472).

Citation Format: Guiqun Yang, Yanping Wang, Haijun Li, Mingming Chen, Yiwei Lin, Xin Sun. JAB-2485: A potent, highly selective small-molecule Aurora kinase A inhibitor that targets cell division [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1645.
Abstract 1677: ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development
Authors: Wang Guoqian , Tang Yao , Lv Tingduo , Ning Jinying , Hao Feng
Published: April 2023

Introduction: KRAS mutations occur in nearly 30% of human cancers, the most frequent ones being G12C, G12D and G12V. The approval of AMG510 in 2021 broke the curse of KRAS’s non-druggability. AMG510 targets the KRAS-G12C mutation and achieves up to 90% disease control rate, but drug resistance quickly develops. KRAS-G12D, the most prevalent and oncogenic KRAS mutation, still lacks inhibitors. MRTX-1133, the first reported highly selective KRAS-G12D inhibitor, is currently in the preclinical phase. Similarly, drug resistance will inevitably develop to KRAS-G12D inhibitors.

Methods: To explore the resistance mechanisms of KRAS-G12D mutation, our group used ASPC-1 cell line, which naturally expresses KRAS-G12D, to generate the ASPC-1-MRTX-1133R cell line using a dose-escalation method after treating cells with a mutagenic agent. Specifically, ASPC-1 cells were treated by MRTX-1133 with increasing dosage for 4 weeks, the remaining live cells were harvested and designated as ASPC-1-MRTX-1133R. Cell survival assay showed that IC50 of ASPC-1-MRTX-1133R is >2000nM, 100-fold more resistant than the parental ASPC-1 cell line (22nM). We identified the potential resistance mechanisms using whole exome sequencing (WES) and RNA-Seq. The resistance to MRTX-1133 of ASPC-1-MRTX-1133R cell line was highly stable after 20 cell passages.

Conclusion: The ASPC-1-MRTX-1133R cell line can be a useful in vitro model in the development of KRAS-G12D inhibitors.

Citation Format: Guoqian Wang, Yao Tang, Tingduo Lv, Jinying Ning, Feng Hao. ASPC-1-MRTX-1133R as a useful cell line model for KRAS-G12D inhibitor development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1677.
Abstract 1684: Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis
Authors: Kwon Mi Jeong , Chae Ha Yeong , Lee So Young , Kang Shin Ung , Jung Tae Woong , Cho Soo Youn , Han Jinil , Jeong Hyojin , Sung Chang Ohk , Shin Young Kee
Published: April 2023

Resistance to platinum-based chemotherapy is one of major causes of therapy failure and tumor recurrence in ovarian cancer patients. However, the molecular mechanism of platinum resistance is not fully understood. Here, we compared gene expression between cisplatin-sensitive and -resistant ovarian cancer cells using gene expression microarray analysis and found the significantly up-regulated expression of SERPINE1 encoding plasminogen activator inhibitor-1 (PAI-1), a serine protease regulating the fibrinolysis and extracelluar matrix, in cisplatin-resistant ovarian cancer cells. The correlation of high PAI-1 expression with low cisplatin sensitivity was confirmed in ovarian cancer cells. PAI-1 overexpression in ovarian cancer cells significantly decreased the sensitivity to cisplatin, whereas PAI-1 down-regulation by SERPINE1 siRNA or PAI-1 inhibitor increased cisplatin sensitivity. PAI-1 inhibited cisplatin-induced apoptosis in ovarian cancer cells by suppressing reactive oxygen species (ROS) production and DNA damage. PAI-1 also decreased cisplatin-induced ferroptosis through the upregulation of GPX4 levels. Furthermore, Kaplan-Meier survival analysis using TGGA data demonstrated that high PAI-1 expression was significantly associated with shorter platinum-free survival of patients with ovarian cancer. Collectively, these results illustrate that PAI-1 promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis, suggesting that targeting PAI-1 increases the sensitivity to cisplatin in ovarian cancer.

Citation Format: Mi Jeong Kwon, Ha Yeong Chae, So Young Lee, Shin Ung Kang, Tae Woong Jung, Soo Youn Cho, Jinil Han, Hyojin Jeong, Chang Ohk Sung, Young Kee Shin. Plasminogen activator inhibitor-1 (PAI-1) promotes cisplatin resistance in ovarian cancer cells by inhibiting ROS-mediated apoptosis and ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1684.
Abstract 1740: CCR5/CCL5 axis inhibition reverses cisplatin-chemoresistance phenotye in gastric cancer cells
Authors: Brebi Priscilla , Reyes Maria Elena , Ili Carmen Gloria , Mora Yuselin , Buchegger Kurt , Riquelme Ismael , Zanella Louise , Lobos-Gonzalez Lorena , Burdiles Camila , Mora-lagos Barbara
Published: April 2023

Gastric cancer (GC) is an important public health problem worldwide. Advanced GC treatment is mainly based in chemotherapy with Cisplatin (CDDP). Unfortunately, the high recurrence rate of GC is predominantly attributable to chemoresistance. The CCR5/CCL5 axis, that participates in inflammatory process, has been associated with the development and progression of cancer. However, its role in GC chemoresistance has not been fully elucidated. The objective of this work was to elucidate the role of CCR5/CCL5 axis on GC chemoresistance cells. AGS R-CDDP was established through a method based on stepwise increasing drug doses and characterized by functional assays. RNA-Sequencing (RNA-seq) was performed on Illumina HiSeq 4000. A fold change >2 and P<0.05 were used as cut-off to choose the differentially expressed genes (DEGs). Gene Ontology (GO) and signaling pathways analysis were analyzed by PANTHER. CCL5 candidate gene was validated by qRT-PCR. Signaling pathways such as STAT3, MAPK and PI3K, associated with cytokines, proliferation and survival were evaluated by western blot assays. Cell viability of CCR5/CCL5 axis inhibition was evaluated in AGS R-CDDP exposed to Chemokine receptor antagonist (CRA) alone and in combination with CDDP. Characterization studies have effectively demonstrated that AGS R-CDDP is a reliable CDDP-resistant model. Bioinformatics analyses identified a total of 189 DEGs associated mainly to molecular functions (GO) involved in CDDP-resistance. The most enriched signaling pathway was the inflammation mediated by chemokine and cytokine which could be involved in the development of CDDP resistance in GC. CCL5 was upregulated in AGS R-CDDP cells. The main signaling pathways associated with CCR5/CCL5 axis were not activated in resistant GC cells compared parental GC cells.The cytotoxicity assays showed that CRA/CDDP combination re-sensitized AGS R-CDDP cells, decreasing cell viability. Our results indicate that CCR5/CCL5 axis induce chemoresistance and CRA/CDDP combination sensitize AGS R-CDDP cells revealing its potential as coadjuvant in GC therapy.

Citation Format: Priscilla Brebi, Maria Elena Reyes, Carmen Gloria Ili, Yuselin Mora, Kurt Buchegger, Ismael Riquelme, Louise Zanella, Lorena Lobos-Gonzalez, Camila Burdiles, Barbara Mora-lagos. CCR5/CCL5 axis inhibition reverses cisplatin-chemoresistance phenotye in gastric cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1740.
Abstract 1755: ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal
Authors: Loh Jia Jian , Wong Tin Lok , Lu Shixun , Yan Helen HN , Siu Hoi Cheong , Xi Ren , Chan Dessy , Kam Max JF , Zhou Lei , Tong Man , Copland John A. , Chen Leilei , Yun Jingping , Leung Suet Yi , Ma Stephanie
Published: April 2023

Targetable drivers governing to 5-fluorouracil and cisplatin (5FU+CDDP) resistance remain elusive due to the paucity of physiologically and therapeutically relevant models. Accordingly, we established 5FU+CDDP resistant intestinal subtype GC patient-derived organoid lines. JAK/STAT signaling and its downstream, adenosine deaminases acting on RNA 1 (ADAR1), are shown to be concomitantly upregulated in the resistant lines. ADAR1 was demonstrated to confer chemoresistance and self-renewal in an RNA editing-dependent manner. WES-seq coupled with RNA-seq identified enrichment of hyperedited lipid metabolism genes in the resistant lines. Mechanistically, ADAR1-mediated A-to-I editing on 3’UTR of stearoyl-CoA desaturase (SCD1) increased binding of KH domain-containing, RNA-binding, signal transduction-associated 1 (KHDRBS1), thereby augmenting SCD1 mRNA stability. Consequently, SCD1 facilitates lipid droplet formation to alleviate chemotherapy-induced ER stress and enhances self-renewal through increasing β-catenin expression. Pharmacological inhibition of SCD1 abrogated chemoresistance and tumor-initiating cell frequency. Clinically, high proteomic level of ADAR1 and SCD1, or high SCD1 editing/ADAR1 mRNA signature score predicts a worse prognosis. Together, we unveiled a novel actionable target to circumvent chemoresistance.

Citation Format: Jia Jian Loh, Tin Lok Wong, Shixun Lu, Helen HN Yan, Hoi Cheong Siu, Ren Xi, Dessy Chan, Max JF Kam, Lei Zhou, Man Tong, John A. Copland, Leilei Chen, Jingping Yun, Suet Yi Leung, Stephanie Ma. ADAR1-mediated RNA editing of SCD1 links lipid metabolism to gastric cancer drug resistance and self-renewal [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1755.
Abstract 1768: Multiplexed shRNA cassettes targeting orthogonal pathways (FAS/PTPN2/TGFBR) enhance the potency of integrated circuit T cells (ICTs) in multiple solid tumor models
Authors: Gardner Thomas J. , Litterman Adam , Singh Brenal K. , Silva Luisa , Hari Mukund , Zhou Stanley , Tang Colin , Joshi Sahil , Gagnon John , Takacsi-Nagy Oliver , Hall Jason , Pope Hans , Zhang James , Gomez Alma , Chen Jeremy , Mohanty Suchismita , Thomas Vince , Quant Nicholas , Millare Beatriz , Casbon Amy-Jo , Bezman Natalie , Gray-Rupp Levi , Boroughs Angela C. , Haining W. Nicholas
Published: April 2023

T cell exhaustion resulting from chronic antigen stimulation and immunosuppression in the tumor microenvironment (TME) limits CAR T efficacy in the solid tumor setting. We have previously shown that engineering therapeutic T cell products using CRISPR-based gene insertion of a dual shRNA cassette targeting Fas and PTPN2 significantly increased antitumor efficacy of Integrated Circuit T cells (ICTs) in ovarian cancer models. We sought to build on this finding to induce additional gene perturbations that improve the efficacy of ICTs. Transforming growth factor (TGF)-b is an immunosuppressive cytokine that potently inhibits T cell responses and is present at high levels in numerous solid tumors, including renal cell carcinoma (RCC). In order to render ICT cells less susceptible to TGF-b-mediated suppression, we developed a quadruple shRNA cassette that simultaneously targets Fas, PTPN2, and TGFBR. Candidate TGFBR-targeting shRNAs were selected for their ability to reduce surface TGFBR receptor expression and impair proximal (pSMAD) or distal (CD103, PD-1) signaling through TGFBR. While single shRNAs against TGFBR did not rescue ICT cell activity in the presence of TGF-b, likely due to partial knockdown of TGFBR signaling, a cassette encoding two shRNAs against TGFBR restored ICT function to similar levels observed in the absence of TGF-b. The quadruple shRNA cassettes targeting Fas/PTPN2/TGFBR significantly enhanced antitumor activity of ICT cells in multiple xenograft tumor models relative to Fas/PTPN2 cassettes. These results demonstrate the utility of multiplexed shRNA strategies to render therapeutic T cells resistant to orthogonal suppressive pathways in solid tumors.

Citation Format: Thomas J. Gardner, Adam Litterman, Brenal K. Singh, Luisa Silva, Mukund Hari, Stanley Zhou, Colin Tang, Sahil Joshi, John Gagnon, Oliver Takacsi-Nagy, Jason Hall, Hans Pope, James Zhang, Alma Gomez, Jeremy Chen, Suchismita Mohanty, Vince Thomas, Nicholas Quant, Beatriz Millare, Amy-Jo Casbon, Natalie Bezman, Levi Gray-Rupp, Angela C. Boroughs, W. Nicholas Haining. Multiplexed shRNA cassettes targeting orthogonal pathways (FAS/PTPN2/TGFBR) enhance the potency of integrated circuit T cells (ICTs) in multiple solid tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1768.
Abstract 177: Expansion of established patient-derived tumoroids in a novel serum-free, Wnt-free media system
Authors: Paul Colin , Balhouse Brittany , Yankaskas Chris , Salen Shyanne , Djikeng Sybelle , Thakuri Pradip Shahi , Dallas Matt , Kuninger David
Published: April 2023

Tumoroid technology enables culture of patient tissue-derived cancer cells in 3D, with retention of key characteristics from the original patient tumor. However, current tumoroid culture relies on labor-intensive media formulations and culture workflows. To address these issues, we have developed the serum- and conditioned medium-free Gibco™ OncoPro™ Tumoroid Culture Medium to enable derivation and expansion of patient-derived lines from multiple cancer indications. The system has been optimized to retain key patient genotypic and phenotypic characteristics during in vitro culture in a Wnt agonist-free system that can be easily adopted and transferred between labs. To test the applicability of our system with previously established tumoroid/cancer organoid models, we procured publicly available cancer models from the National Cancer Institute Patient-Derived Models Repository (NCI PDMR). Multiple colorectal, lung, pancreas, and head and neck tumoroid models were tested, including tumoroids originally derived in conditioned medium containing Wnt-3A, R-spondin 3, and Noggin. Cells were assessed for survival, growth, and fidelity to starting material in both OncoPro Tumoroid Culture Medium and in PDMR-recommended homebrew media. Growth and morphology of tumoroid cells was monitored and was comparable between culture conditions. To test for genetic stability of cultures over time, the mutational status of organoids expanded in each condition was characterized using targeted NGS. Both SNV allelic frequency and ploidy values were conserved from initial starting material following expansion to cryopreservation-competent banks (>10e6 cells). Gene expression levels across over >20,000 human RefSeq genes were compared between culture methods and showed high (>0.9) correlation, and Wnt-related signaling pathways were not differentially regulated between media types. In select cases, tumoroid cells expanded in each condition were also analyzed by flow cytometry using optimized antibody panels and protocols. Total cell viability and expression of EpCAM, CD45, CD31, smooth muscle actin, vimentin, CDX2, CEACAM, and cytokeratin 7 was nearly identical across culture conditions. Taken together, our approach represents a simple and effective method to expand and maintain patient-derived human cancer organoids in vitro, with no clear adverse effects from moving to a Wnt-free system.

Citation Format: Colin Paul, Brittany Balhouse, Chris Yankaskas, Shyanne Salen, Sybelle Djikeng, Pradip Shahi Thakuri, Matt Dallas, David Kuninger. Expansion of established patient-derived tumoroids in a novel serum-free, Wnt-free media system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 177.
Abstract 1804: Durable eradication of tumors by single injections of a pHLIP-STING agonist
Authors: Engelman Donald M. , Reshetnyak Yana K. , Andreev Oleg A.
Published: April 2023

Purpose: pHLIPs (pH-Low Insertion Peptides) target cell surface acidity resulting from the metabolism of cells in a solid tumor. The acidity causes pHLIPs to insert as transmembrane helices, and attached cargoes can be delivered into targeted cells. STING agonists can trigger an immune response when they are inside cells. pHLIP targeted delivery of a STING agonist (STINGa) effectively triggers cytokine secretion to mobilize the immune system to eradicate tumors while avoiding side effects.

Experimental Procedures: Constructs consisting of a pHLIP peptide (Var3) linked to a STINGa (diABZI) via a self-immolating linker were synthesized and characterized. Activation of the STING pathway by the agent was confirmed in cells. Small (100 mm3) and large (400-700 mm3) tumors were grown in female Balb/c mice following flank injections of CT26 colorectal cancer cells. Randomized groups of mice were injected i.p. or i.v. with pHLIP-STINGa made with L- or D- amino acid pHLIP peptides, STINGa alone, pHLIP alone or vehicle. Tumor size and body weight were then measured 3 times per week. The durability of the response to the agent was tested by a second injection of CT26 cells after 60 days. In separate experiments, the identities of targeted immune and stromal cells, the production of cytokines, the PK, tumor targeting and biodistribution were assessed.

Results and Conclusions: pHLIP extends the lifetime of a STINGa in the blood 6-fold and delivers STINGa to acidic cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), myeloid derived suppressor cells (mMDSCs), and dendritic cells (DCs). The resulting activation of cytokines within the tumor microenvironment (TME) triggers the eradication of small and large CT26 tumors in mice after a single dose of pHLIP-STINGa. The tumor stroma was destroyed, intratumoral hemorrhage developed, and the TME pH increased, which is important for the efficient cytotoxic activity of immune cells. Further, no tumors developed in 20 out of 25 tumor-free mice re-challenged by an additional injection of cancer cells. The therapeutic effect on CT26 tumors was insignificant in nude mice lacking T-cells. Inhibition of MHC-I negative B16F10 melanoma tumor growth was also observed in Balb/c mice. Thus, targeted delivery of the STINGa to the tumor stroma and TAMs activates signaling, potentially resulting in the recruitment and infiltration of both T-cells and NK-cells, which gain access to the tumor core. The cytotoxic activity of immune cells is enhanced, and immune memory is developed.

Citation Format: Donald M. Engelman, Yana K. Reshetnyak, Oleg A. Andreev. Durable eradication of tumors by single injections of a pHLIP-STING agonist [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1804.
Abstract 1806: Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r)
Authors: Dufort Fay , Leitheiser Christopher J. , Ho Kathleen , Ezell Tucker , Rezvaya Alexandra , Brown Peter , Chen Liuhong , Brandish Philip , McDonnell Kevin , Skynner Michael , Keen Nicholas
Published: April 2023

The tumor specific activation of natural killer (NK) cells with Bicycles is an area of active investigation in immune oncology. NK cells are highly responsive immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Bicycles are small (ca.1.5kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have applied the Bicycle platform technology to discover and evaluate a new class of fully synthetic molecules termed NK tumor immune cell agonists (NK-TICA®). The NK-TICA® consists of chemically coupled Bicycles® that bind specifically to the key activating receptor, NKp46, and to tumor antigens, that results in highly potent, antigen-dependent receptor activation and NK cell activation. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function in vitro. With Bicycle’s novel NK-TICA® compound, we demonstrate the engagement of NK cells, the specific activation and function of NK cells, and enhanced tumor cytotoxicity in a tumor target- and dose-dependent manner. In conclusion, NK-TICAs drive NK cell-mediated tumor cell killing and cytokine production in vitro and as such have the potential to catalyze the development of durable anti-tumor immunity in tumor types not well served by current therapies. We hypothesize that utilization of Bicycle NK-TICA® as a multifunctional immune cell engager will promote the modulation of NK cells, as well as the infiltration and anti-tumor activity of NK cells in solid tumors.

Citation Format: Fay Dufort, Christopher J. Leitheiser, Kathleen Ho, Tucker Ezell, Alexandra Rezvaya, Peter Brown, Liuhong Chen, Philip Brandish, Kevin McDonnell, Michael Skynner, Nicholas Keen. Modulation of natural killer cell immune response to tumor with novel synthetic tumor -immune cell agonist, NK-TICA(r) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1806.
Abstract 1834: Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs
Authors: Darragh Laurel B. , Pham Tiffany T. , Knitz Michael M. , Nguyen Alexander , Mukdad Laith A. , Alhiyari Yazeed , John Maie St. , Karam Sana D.
Published: April 2023

Perineural invasion (PNI) and nerve density within the tumor microenvironment (TME) have long been associated with worse outcomes in head and neck squamous cell carcinoma (HNSCC). We investigate how nerves within the tumor microenvironment impact the adaptive immune system and tumor growth. RNA sequencing and proteomics data led us to identify cholinergic nerves as the potential drivers of tumor growth in human and mouse HNSCC. Using three syngeneic orthotopic murine models of HPV-unrelated HNSCC, experimental and pharmacologic manipulation of cholinergic output, and knockout mouse models, we discovered that activation of cholinergic nerves accelerate tumor growth by directly acting on the adaptive immune system. Cholinergic nerve release of calcitonin gene-related peptide (CGRP) directly inhibited CD8 T cell activity in vitro, and blocking cholinergic nerves pharmacologically or genetically increased CD8 T cell activity in vivo. These data support therapeutic translation of cholinergic nerve targeting of CGRP release to enhance antitumor immune response within the HNSCC TME.

Citation Format: Laurel B. Darragh, Tiffany T. Pham, Michael M. Knitz, Alexander Nguyen, Laith A. Mukdad, Yazeed Alhiyari, Maie St. John, Sana D. Karam. Cholinergic nerve release of CGRP increases tumor growth in HNSCC by suppressing TILs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1834.
Abstract 1870: VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers
Authors: Wong Oi Kwan , Wang Xinhua , Chen Xiaocheng , Post Leonard
Published: April 2023

CD47/SIRPα axis is an important checkpoint of innate immune system and is often exploited by tumor cells to evade host immune surveillance. In recent years, therapies such as anti-CD47 monoclonal antibodies (mAbs) and SIRPα fusion proteins that target this axis have garnered much attention. Although exciting clinical activities have been observed in hematological cancers, responses in solid tumors are less impressive and often require complex combination strategies.

We previously described a novel CD47xEpCAM bispecific antibody, VBI-003, built on a human IgG1 backbone to harness the power of blocking CD47/SIRPα pathway while preserving the effector functions of IgG1 Fc (J ImmunoTher Cancer 2021;9:doi: 10.1136/jitc-2021-SITC2021.274). The bispecific design aims to improve selectivity so that SIRPα blocking and stable binding occur selectively on tumor cells where both CD47 and EpCAM are present. In vitro studies show that VBI-003 exhibits minimal red blood cell binding and does not cause hemagglutination, in contrast to benchmark CD47 mAb. VBI-003 has potent single agent activity in cell line derived xenograft (CDX) models of gastric and esophageal cancers. Here, we further explored the anti-tumor activities of VBI-003 in areas with great unmet needs such as small cell lung cancers (SCLC) and colorectal cancers (CRC).

Gene expression analysis from public datasets reveals frequent expression of CD47 and EpCAM in SCLC and CRC tumors. Flow cytometry studies confirmed co-expression of CD47 and EpCAM on SCLC and CRC cell lines. Furthermore, in vitro assays showed that VBI-003 has potent EpCAM dependent SIRPα blocking, antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity activities towards SCLC and CRC cell lines. Moreover, VBI-003 demonstrated potent single agent activity in multiple CDX models of SCLC with tumor regression and often outperformed benchmark CD47 mAb. Significant tumor growth inhibition was observed in colorectal cancer models post VBI-003 treatment, with additional activity by combination with standard of care chemotherapies. VBI-003 synergized with irinotecan and outperformed monotherapy groups in CDX models of CRC. In conclusion, VBI-003 has potent single agent activity in SCLC tumor models and combined synergistically with irinotecan in CRC models. Our data support further investigation of VBI-003 as a treatment for CD47 and EpCAM expressing SCLC and CRC.

Citation Format: Oi Kwan Wong, Xinhua Wang, Xiaocheng Chen, Leonard Post. VBI-003, a CD47xEpCAM bispecific antibody as a potential treatment for colorectal and small cell lung cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1870.
Abstract 1898: Racial/ethnic disparities in stage at diagnosis among women with cervical cancer in Texas: Mediating effects of neighborhood-level socioeconomic deprivation
Authors: Sokale Itunu O. , Oluyomi Abiodun O. , Thrift Aaron P.
Published: April 2023

Background: Although mortality from cervical cancer has declined steadily in the U.S. since the advent of population-based screening in the 1970s, the benefit has not reached all racial/ethnic groups of patients equally. This study examined the underlying role of neighborhood-level socioeconomic disadvantage as a potential mediator of the association between race/ethnicity and being diagnosed with late-stage versus early-stage cervical cancer. Methods: We analyzed Texas Cancer Registry data for cervical cancer cases diagnosed among women aged 18 or older from 2010 to 2018. Cervical cancer cases were categorized as early or late stage at diagnosis. First, we used a stepwise hierarchical logistic regression model to examine the associations between race/ethnicity and stage at diagnosis. Then, we performed causal mediation analyses using the counterfactual framework approach to estimate the direct, indirect (mediated), and total effects, and percent mediated. Results: Of the 9525 women with cervical cancer, 4869 (2200 non-Hispanic White (NHW) (45.2%), 720 non-Hispanic Black (NHB) (14.8%), 1800 Hispanic (37.0%)) had late-stage cervical cancer at diagnosis (overall, 51.1%). Women 65 years or older, NHB, Hispanic, with Medicaid/Medicare, uninsured, and those who reside in more deprived neighborhoods were more likely to present with advanced cervical cancer at diagnosis (p <0.001). Compared to NHW women (11.8%), NHB (28.5%) and Hispanic (34.4%) women were more likely to live in most deprived neighborhoods and had greater odds of late-stage cervical cancer diagnosis (unadjusted odds ratios 1.49 (95% CI 1.31-1.69) and 1.20 (95% CI 1.10-1.31), respectively). In the age-adjusted mediation analysis, 23.1% and 52.2% of the disparity were attributable to higher disadvantages among NHB and Hispanic women, respectively.Conclusions: Results of mediation analyses suggested that area-level deprivation explained some of the racial/ethnic disparities in stage at diagnosis of cervical cancer among NHB and Hispanic women versus NHW women.Impact: These findings can be applied to develop targeted and race-specific interventions to improve early diagnosis and treatment of cervical cancer for cancer care equity.

Citation Format: Itunu O. Sokale, Abiodun O. Oluyomi, Aaron P. Thrift. Racial/ethnic disparities in stage at diagnosis among women with cervical cancer in Texas: Mediating effects of neighborhood-level socioeconomic deprivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1898.
Abstract 19: Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte
Authors: Yap Jiajun , Yuan Jimin , Chen Bin Gao , Ng Wan Hwa , Sim Yuen Rong M. , Goh Kah Chun , Hu Jiancheng
Published: April 2023

Hairy cell leukemia (HCL) is a B-lymphoma induced by BRAF(V600E) mutation. However, introducing BRAF(V600E) in B-lymphocytes fails to induce hematological malignancy, suggesting that BRAF(V600E) needs concurrent mutations for driving HCL ontogeny. To resolve this issue, here we surveyed the human HCL genomic sequence data. Together with previous reports, we speculated that tumor suppressor, Trp53, P27, or pTEN restricted the oncogenicity of BRAF(V600E) in B-lymphocytes, whose loss-of-function facilitates the BRAF(V600E)-driven HCL ontogeny. Using genetic mice models, we demonstrated that indeed BRAF(V600E)KI together with Trp53KO or pTENKO in B-lymphocytes induced chronic lymphoma with pathological features of human HCL. To further understand cellular programs essential for HCL ontogeny, we next profiled the gene expression of leukemic cells isolated from BRAF(V600E)KI and Trp53KO or pTENKO mice, and found that these leukemic cells had similar but different gene expression signatures that resemble that of M2 or M1 macrophages. In addition, we examined the expression signature of transcription factors/regulators required for germinal center reaction and memory B cell versus plasma cell differentiation in these leukemic cells and found that most transcription factors/regulators essential for these programs were severely inhibited, which illustrates why hairy cells are arrested at a transitional stage between activated B cells and memory B cells. Together, our study has uncovered concurrent mutations for HCL ontogeny, revealed the B cell origination of hairy cells as well as molecular basis that underlies unique pathological features of this disease, and hence has important implications in both HCL research and clinic treatment.

Citation Format: Jiajun Yap, Jimin Yuan, Bin Gao Chen, Wan Hwa Ng, Yuen Rong M. Sim, Kah Chun Goh, Jiancheng Hu. Braf(v600e) mutation together with loss of trp53 or pten drives the origination of hairy cell leukemia from b-lymphocyte [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 19.
Abstract 1941: Barriers and effective interventions to engage Latinas' participation in breast cancer clinical trials
Authors: Padilla Monica J. , Karczmar Gregory
Published: April 2023

Breast cancer is the most diagnosed cancer among Latina women and is the leading cause of cancer-related death among Latinas (16.6%). While The Latino population is one of the fastest-growing populations in the US, they are severely underrepresented in clinical trials. Latinos make up 17% of the population but only 1% of clinical trial participants. Of clinical trials published covering 2001-2010, Latinos’ enrollment constituted only 2.2% of accrued participants. The percentage of Latino participants narrows down when we separate by gender. The goal of this study is to examine the prevalence of breast cancer-related barriers among Latinas and to determine the extent to which these barriers might influence Latinas enrolling in breast cancer clinical trials. If language and religion are the reason Latinas enroll less in breast cancer clinical trials, then increasing the availability of translated materials and a priest of a Catholic Church advertising the breast cancer studies will increase the enrollment rate of Latinas. Semi-constructed interviews were conducted with two Latino organizations to understand current barriers Latina’s face within the medical field. Based on these findings, I conducted an intervention at Our Lady of Tepeyac Church consisting of an information booth, making an announcement regarding Research Study 9127, and having bilingual Latinas available to give out more information while helping them enroll in Research Study 9127. At the end of the church intervention, 33 Latinas were enrolled in Research Study 9127, seeing a 550% increase in Latinas participating in Research Study 9127. Latinx women remain severely underrepresented in breast cancer clinical trials, thus limiting the generalizability of cancer clinical research, but interventions across churches would lead to improvements in general cancer knowledge, breast cancer screening practices, and intentions to enroll in clinical trials. This study can inform efforts to increase clinical trial participation in Latinas by highlighting important motivators to participation specific to Latinas and informing future interventions aimed at encouraging participation in clinical trials in a culturally sensitive and effective way.

Citation Format: Monica J. Padilla, Gregory Karczmar. Barriers and effective interventions to engage Latinas' participation in breast cancer clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1941.
Abstract 1968: A multiomic spatial atlas of breast cancer in women of African ancestry
Authors: Plummer Jasmine T. , Nikulina Nadezhda , Omotoso Ayodele , Burnett Destiny , Coelho Priscilla , Badal Simone , Hurley Judith , Gomez Carmen , Ji Ha Yeun , Marcao Maycon , Segato Felipe Dezem , Braubach Oliver , George Sophia
Published: April 2023

The US Black population consists of both US-born Black and immigrant Black populations from the Caribbean and Africa. Normal tissues in Black individuals, independent of their country of birth or residence, are woefully understudied. Yet, Black individuals disproportionately develop aggressive pathologic diseases and are treatment refractory or resistant, thus leaing to premature deaths. In women, breast cancer is more common among US Black women, and the most common non-viral driven cancer in African and Caribbean countries. Furthermore, Black women develop this disease younger than other ancestral groups and have a higher incidence aggressive pathologies, such as metaplastic and triple-negative breast cancer. With the African-Caribbean Cancer Consortium (AC3) and Transatlantic Gynecologic Cancer Research Consortium, we have created a multiomic spatial atlas of triple-negative and other breast cancers across Africa, the Caribbean, and among US-Black individuals. We performed ultrahigh-plex RNA and protein spatial phenotyping on the PhenoCycler-Fusion (PCF). The PCF is a fast end-to-end spatial biology platform that enables whole-slide spatial readouts of RNA and protein moieties at single-cell resolution. Multiomic spatial phenotyping of tissues allowed for the detection of novel cell populations associated with a given African ancestry linking unique immune/stromal cell types to the outcome and severity of breast cancer. Here, we aim to develop a benchmark that confidently measures and interprets ancestral genomic differences at the cellular level. Deciphering the relationship between African ancestry, aggressive disease biology, and early onset will enable the characterization of the tissue composition and the proportion of cell sub-populations implicated in tumorigenesis and the interplay with germline genetics.

Citation Format: Jasmine T. Plummer, Nadezhda Nikulina, Ayodele Omotoso, Destiny Burnett, Priscilla Coelho, Simone Badal, Judith Hurley, Carmen Gomez, Ha Yeun Ji, Maycon Marcao, Felipe Dezem Segato, Oliver Braubach, Sophia George. A multiomic spatial atlas of breast cancer in women of African ancestry [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1968.
Abstract 1972: Potential predictors of prostate cancer screening: Findings from the MiCaP research digest study
Authors: Machuca Jessica Otero , Fathi Parisa , Lee Daniel , Walsh-Childers Kim , Odedina Folakemi
Published: April 2023

Introduction: Black men are disproportionately affected by prostate cancer (CaP) and havebeen found to experience more aggressive forms of cancer. The Minority Prostate Cancer(MiCaP) Research Digest is a dissemination platform with the goal of spreading community-based and culturally relevant ways to provide prostate cancer discoveries, interventions, andclinical trials among Black men. In collecting pretest data, the MiCaP team was also able tocollect data on whether participants had been tested for CaP in the last year. We were also ableto collect data on various social determinant variables to test for association.

Methods: Black men living in the United States ages 35 to 70 were recruited for this studythrough community-based methods. Participants were randomly assigned to an interventiongroup that received the MiCaP information material and a control group that watched a generalvideo. Both groups received baseline and follow-up surveys to assess their knowledge relatedto CaP clinical trials, testing, and treatment. Associations of characteristics from the baselinesurvey were evaluated using logistic regression models.

Results: A total of 220 responses are included in this dataset. The majority of participants wereborn in the United States (93.06%), single (49.52%), attended/graduated college (35.65%),between 60 and 69 years (25.58%), had full-time employment (52.07%), and had a householdincome between 20,000 and 39,999 (21.66%). Only about 35% had read or heard about clinicaltrials within the last year. Logistic regression found a positive association between the followingvariables and getting tested for prostate cancer in the past year: if participants had heard ofcurrent prostate cancer research or discoveries, if an immediate family member had beendiagnosed with prostate cancer, age, and level of education. No association was found betweeninsurance status, utilization of healthcare, clinical trial participation, or clinical trial knowledge.

Conclusion: There is an association between being aware of CaP discoveries, diagnosis of familymembers, education, and age with prostate cancer screening. Future work should be done tofurther explore this association and how to overcome the barriers those determinants mightprovide in screening. These data and future data on this can be used to further community-based interventions delivered in culturally relevant ways with the goal of encouraging positivehealth behaviors to reduce CaP in Black men.

Citation Format: Jessica Otero Machuca, Parisa Fathi, Daniel Lee, Kim Walsh-Childers, Folakemi Odedina. Potential predictors of prostate cancer screening: Findings from the MiCaP research digest study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1972.
Abstract 1982: Exploring the impact of metastatic breast cancer support group in Nigeria
Authors: Chidebe Runcie C. , Nwosu-Zitta Theodora , Orji Mary-Gloria A. , Banwo-Fatai Khadijat , Agha Agha A. , Esiaka Darlingtina K. , Orjiakor Tochukwu C.
Published: April 2023

Background: Over 70% of breast cancer patients in Nigeria present metastatic/advanced breast cancer (MBC). An estimated 90% of breast cancer deaths are as a result of metastatic disease, either at diagnosis or recurrence. MBC is associated with severe burden to the patient, family, healthcare delivery system and the society at large. Women living with MBC face many challenges ranging from poor access to MBC information, untreated pain, frequent break-down of radiotherapy machines and absence of peer support.

Method: In this research, we set up the first metastatic breast cancer support group in Abuja. The group meet once every month on a face-to-face basis and also uses WhatsApp group for regular meaningful engagement. We explored the impact of the group on the patient’s quality of life (QoL) using a focused group discussion (FGD). Eighteen (18) patients participated in the two sessions of FGD.

Result: Many of the patients report that the support group provides a culture of love and strength over their death anxiety, especially meeting other patients who have lived with MBC longer. They also report to have found peer support on the online WhatsApp group.

Citation Format: Runcie C. Chidebe, Theodora Nwosu-Zitta, Mary-Gloria A. Orji, Khadijat Banwo-Fatai, Agha A. Agha, Darlingtina K. Esiaka, Tochukwu C. Orjiakor. Exploring the impact of metastatic breast cancer support group in Nigeria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1982.