bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1648: Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors
Authors: Gao Mingming , Li Zhentian , Fan Qipeng , Pan Jun , Bai Yu , Zhang Hewen , Li Yu , Wu Yongzhong , Liu Phillip C.C. , Wu Liangxing , Yao Wenqing , Wang Hui
Published: April 2023

PARP1/2 inhibitors are FDA approved for treatment of cancers such as ovarian, prostate, pancreas and breast with greatest activity against tumors harboring BRCA1 or 2 mutation or homologous recombination deficiency (HRD). A shared adverse event that contributes to a narrow therapeutic index and limits combination potential is hematologic toxicity. First generation PARP inhibitors are not selective against PARP2, which has been shown to play a role in the survival of hematopoietic progenitor cells in animal models. However genetic studies suggest that the synthetic lethality from PARP trapping with HRD is primarily dependent on PARP1. We hypothesized that a potent and selective PARP1 inhibitor and trapper would achieve equivalent anti-tumor activity as non-selective PARP inhibitors while alleviating toxicities caused by PARP2 inhibition.

SNV-001 is a novel, proprietary, potent, and selective PARP1 inhibitor and trapper. In PARylation assays, SNV-001 inhibited PARP1 activity with low nanomolar potency and displayed greater than 500-fold selectivity against PARP2. In cellular PARP trapping assays, SNV-001 potently trapped PARP1 on DNA in a dose-dependent manner but did not trap PARP2 up to 25 µM. Functionally, SNV-001 exhibited selective growth inhibitory activity against cancer cell lines with impaired HR function. In anti-proliferation and colony formation assays of BRCA-mutant cell lines including MDA-MB-436 (BRCA1 deficient) and DLD1 (BRCA2 knockout), SNV-001 inhibited cell growth and colony formation with single-digit nM IC50 values while having minimal effects against BRCA-WT cells. In a subcutaneous MDA-MB-436 xenograft tumor model, SNV-001 administered orally once daily achieved dose-dependent inhibition of PARylation in vivo. Furthermore, SNV-001 showed dose-dependent tumor growth inhibition using low daily doses with greater efficacy compared to olaparib dosed at 100 mg/kg once daily. In the cohort receiving a higher dose of SNV-001, all animals showed complete regression after 35 days of treatment without any clinical signs of toxicity.

In summary, we have discovered SNV-001, a potent and selective PARP1 inhibitor and trapper that shows excellent activity against cancer models with HRD in vitro and in vivo. These data support advancement of SNV-001 into clinical development for patients with tumors characterized by HRD.

Citation Format: Mingming Gao, Zhentian Li, Qipeng Fan, Jun Pan, Yu Bai, Hewen Zhang, Yu Li, Yongzhong Wu, Phillip C.C. Liu, Liangxing Wu, Wenqing Yao, Hui Wang. Discovery of a potent and selective PARP1 inhibitor and trapper with anti-tumor activities in HRD tumors [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 1648.
Abstract 1655: Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer
Authors: Johnson Hannah , Singh Amandeep , Raza Asif , Sha Congzhou M. , Dokholyan Nikolay V. , Narayan Satya , Sharma Arun K.
Published: April 2023

Protein phosphatase 2A (PP2A) is a diverse serine/threonine phosphatase that accounts for 50-70% of all serine/threonine phosphorylation in the cell. Due to the inactivation of PP2A in cancer, many of the cellular processes that PP2A regulates are aimed towards tumor progression. As such, the therapeutic targeting of PP2A in cancer is becoming a popular research avenue in the development of new chemotherapeutics. Currently, there have been a few PP2A activators observed to inhibit tumor progression in vitro and in vivo; however, these compounds have shown to have poor bioavailability, such as NSC49L, or uncertainty towards their ability to activate PP2A, as is the case with iHAP1. These hindrances demonstrate a need for further optimization of these molecules in order to produce a PP2A activator capable of inhibiting cancer without these limitations. As such, we have designed a series of compounds utilizing molecular modeling and fragment-based drug design based upon the known PP2A activators, NSC49L and iHAP1. These compounds were assessed for their ability to inhibit colon cancer (CRC) cells and FOLFOX-resistant CRC cells, where PPA24 was identified as the lead compound. The dose-response curves identified IC50 values in the range of 2.36-6.75µM for PPA24 across four CRC cell lines (HCT116, HT29, DLD1, and SW480) and two FOLFOX-resistant CRC cell lines (FOLFOX-HCT116 and FOLFOX-HT29), displaying more cytotoxicity than both the parent compounds and the other compounds in the series. Molecular docking recognized lower binding energies occurring during the association of PP2A with PPA24 than with either NSC49L or iHAP1. When examining the in vitro effect of PPA24 on stimulating PP2A activation, it was found that PPA24 significantly induced PP2A activity 2-3-fold higher than NSC49L or iHAP1. Likewise, PPA24 was able to induce apoptosis dose-dependently in both CRC and FOLFOX-resistant CRC cells. As PP2A is known for regulating the cell cycle progression, further exploration revealed PPA24 able to induce cell cycle arrest at the G2/M phase. And PP2A, being known as a regulator for many cellular processes, can be activated to assist in the degradation and inactivation of many signaling proteins such as c-myc, GSK3β, and ERK, which was observed in CRC cells treated with PPA24. Together, these results signify the potential of PPA24 to act as a novel PP2A activator in the treatment of CRC and FOLFOX-resistant CRC.

Citation Format: Hannah Johnson, Amandeep Singh, Asif Raza, Congzhou M. Sha, Nikolay V. Dokholyan, Satya Narayan, Arun K. Sharma. Discovery of a novel PP2A activator as a potential therapeutic for FOLFOX resistant colon cancer [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 1655.
Abstract 1679: Unraveling the function of TRAF2 and NCK interacting kinase (TNIK) in high-grade serous ovarian cancer
Authors: Puleo Noah , Cusato Michele , Carvette Dylan , Husdon Chantelle , DiFeo Analisa
Published: April 2023

The large majority of high grade serous ovarian cancer (HGSOC) patients will eventually become resistant to platinum-based chemotherapy, highlighting the urgent need to develop novel therapeutics targeting recurrent, platinum-resistant disease. To study this, our lab generated two patient derived platinum-resistant tumor spheres from platinum-sensitive primary patient cells to better understand the biology behind recurrent disease and identify novel therapeutic targets. Utilizing an artificial intelligence (AI) powered model, we screened a library that consisted of compounds predicted to target known or postulated resistance mechanisms and involved a novel therapeutic target. From this screen, we identified a TNIK kinase inhibitor as the only compound to effectively kill HGSOC spheres while sparing non-malignant fallopian tube cells. TNIK plays a key role in Wnt pathway activation, which our lab has previously shown to be critical in driving cancer stemness and epithelial ovarian cancer platinum resistance. Additionally, patient data shows that TNIK is amplified in ovarian cancer more than any other cancer type and is highly activated in ovarian cancer patients. We found that this compound was able to decrease overall Wnt activity in our platinum-resistant cells and could resensitize our platinum-resistant cells to cisplatin. This work demonstrates the abilities of using AI to expedite the drug discovery process as well as uncover novel therapeutic targets which may lead to future therapeutic strategies for HGSOC patients who no longer respond to standard of care platinum chemotherapy.

Citation Format: Noah Puleo, Michele Cusato, Dylan Carvette, Chantelle Husdon, Analisa DiFeo. Unraveling the function of TRAF2 and NCK interacting kinase (TNIK) in high-grade serous ovarian cancer [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 1679.
Abstract 1688: Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer
Authors: Morita Ryuichi , Ishikawa Takeshi , Matsumura Shinya , Sakakida Tomoki , Yoshida Juichiro , Doi Toshifumi , Hirose Ryohei , Inoue Ken , Dohi Osamu , Yoshida Naohisa , Uchiyama Kazuhiko , Takagi Tomohisa , Konishi Hideyuki , Naito Yuji , Itoh Yoshito
Published: April 2023

Introduction: V-ATPase is highly expressed in cancer cells and has been shown to be involved in the transformation of normal cells into cancer cells, invasion of tissues, survival of cancer cells, and the formation of drug resistance. The use of proton pump inhibitors (PPIs) as V-ATPase inhibitors has been shown to enhance the efficacy of chemotherapy in some cancers.

Material and Method: We investigated the effect of proton pump inhibitors on esophageal squamous cell carcinoma, one of the major causes of cancer mortality in Japan. First, three PPIs at various concentrations (lansoprazole, esomeprazole, and bonoprazan) and pyrimidine fluoride (5-FU), a key drug in chemotherapy for esophageal cancer, were used as basic medical agents. Human esophageal squamous cell lines, KYSE50 and KYSE70, were prepared and treated with the above drugs, and cell viability assays were performed using Cell Counting Kit 8 for 72 hours. We then performed a retrospective clinical study of 40 patients with clinical stage IV esophageal squamous cell carcinoma treated with the drugs at Kyoto Prefectural University of Medicine Hospital in Japan.

Result: In cell survival assays, PPIs showed significantly enhanced cytotoxic effects of pyrimidine fluoride on all cell lines compared with those not treated with PPIs. Clinical data showed no difference in the incidence of treatment-related adverse events between the PPI and non-PPI groups. The response rate after two courses of chemotherapy was 66.7% in the PPI group and 40.9% in the non-PPI group (p=0.102). Kaplan-Meier analysis showed improved OS in patients treated with PPIs (log rank test p=0.032), and multivariate analysis showed that PPI use was associated with a more favorable OS (p=0.009,HR 0.33,95% CI 0.12-0.76 ).

Conclusion: In the chemotherapy of esophageal squamous cell carcinoma, the use of PPIs may enhance the cytotoxic effect of the key drug, pyrimidine fluoride, while ensuring safety, and may lead to better therapeutic efficacy.

Citation Format: Ryuichi Morita, Takeshi Ishikawa, Shinya Matsumura, Tomoki Sakakida, Juichiro Yoshida, Toshifumi Doi, Ryohei Hirose, Ken Inoue, Osamu Dohi, Naohisa Yoshida, Kazuhiko Uchiyama, Tomohisa Takagi, Hideyuki Konishi, Yuji Naito, Yoshito Itoh. Proton pump inhibitors as a potential combination therapy with existing chemotherapy for esophageal cancer [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 1688.
Abstract 1747: Targeting metabolic and epigenetic programs to re-sensitize glioblastoma to chemotherapy
Authors: Rowland Emma , Walter Jordan , Jermakowicz Anna , Suter Robert , Riggins Rebecca , Ayad Nagi
Published: April 2023

Treatment options for glioblastoma (GBM) are limited. Prognosis remains dismal, with an 18 month on average survival rate following diagnosis due to treatment resistance and disease recurrence. The goal of this project is to investigate hallmarks of cancer progression that contribute to temozolomide (TMZ) resistance, a first tine treatment for GBM.

Two signaling pathways were investigated in TMZ-sensitive and -resistant GBM cell lines and in primary and recurrent patient-derived xenograft (PDX) tumor cells by genetically and pharmacologically inhibiting methionine adenosyltransferase 2A (MAT2A) and adenosylhomocysteinase (AHCY). Cell growth and survival were assessed by measuring protein expression of proliferation, oxidative stress and cell cycle arrest markers. EPIC array analysis and targeted bisulfite sequencing were conducted to identify changes in genome-wide and specific CpG island methylation. The Seahorse XF Analyzer measured mitochondrial respiratory capacity and oxidative metabolism. Induced pluripotent stem cell organoids were co-cultured with PDX tumor cells to determine if treatments mitigate tumor cell invasiveness.

Compared to parental cells (PC), MAT2A gene expression was increased by 1.7-fold in acquired resistant and de novo resistant GBM cells (RC) [(transcript per million): PC, 7386 ± 412; RC, 12941 ± 1023; n=2; p=2.10e-8].Compared to TMZ-sensitive cells (TS), TMZ-resistant cells (TR) demonstrated a 56% increase in baseline oxygen consumption rate [(pmol/min): TS, 179 ± 6.7; TR, 279 ± 13; n=18; p=.0012] and 64% increase in maximal respiratory capacity [(pmol/min): TS, 403 ± 29; TR, 659 ± 35; n=6; p<.0001]. Both primary and recurrent GBM cells were subject to select MAT2A and AHCY inhibitor compounds and EC50s were determined. Recurrent cells demonstrated a vulnerability to TMZ-generated cell death both by genetically knocking down and pharmacologically inhibiting MAT2A and AHCY.

MAT2A and AHCY contribute to TMZ resistance and recurrence by dysregulating methylation programs and upregulating antioxidant programs, respectively. These findings provide a foundation for developing novel combinatory therapeutic strategies and inform clinical studies intended to augment the practically negligible rate of remission for GBM and improve treatment outcomes for cancer patients.

Citation Format: Emma Rowland, Jordan Walter, Anna Jermakowicz, Robert Suter, Rebecca Riggins, Nagi Ayad. Targeting metabolic and epigenetic programs to re-sensitize glioblastoma to chemotherapy [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 1747.
Abstract 1809: ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality
Authors: Jeay Sébastien , Diethelm Stefan , Knopf Agnes , Goxe Marie , Daugan Marie , Erupathil Julie , Pothier Julien , Pozzi Davide , Sifferlen Thierry , Wyder Lorenza , Lyothier Isabelle , Corminboeuf Olivier , Lehembre Francois , Renz Imke , Meyer Dominique
Published: April 2023

Prostaglandin E2 (PGE2) binds to four G-protein-coupled EP receptors, of which both EP2 and EP4 are abundantly expressed by tumor-infiltrating immune cells including DCs, NK cells, Tregs, cytotoxic T cells and TAMs. Signaling via EP2 and EP4 is immunosuppressive, preventing the mounting of effective anti-tumor immune responses leading to tumor immune escape and tumor progression. Currently, several EP4 selective antagonists and an EP2/4 dual antagonist are being developed for anti-cancer immunotherapy. Using a combination of EP2 and EP4 selective antagonists in different tumor mouse models, we could demonstrate that dual EP2/EP4 blockade is more effectively activating anti-tumor immunity compared to targeting either receptor alone. The concurrent inhibition of EP2 and EP4 resulted in tumor regression and induction of immunological memory. Together with published data showing similar findings, our results suggest that simultaneous targeting of EP2 and EP4 could be a promising new therapeutic approach to overcome cancer immune evasion. Idorsia Pharmaceuticals has identified ACT-1002-4391 as a novel, potent antagonist of EP2 and EP4 receptors with an excellent duality profile. In vitro, ACT-1002-4391 is capable of modulating immune cell proliferation and/or function and is superior to EP2 or EP4 selective inhibition in that respect. In vivo, ACT-1002-4391 displays strong and dose-dependent single agent anti-tumor efficacy in a syngeneic mouse tumor model. Based on the excellent selectivity and duality profile, ACT-1002-4391 will be advanced into clinical development by Idorsia Pharmaceuticals.

Citation Format: Sébastien Jeay, Stefan Diethelm, Agnes Knopf, Marie Goxe, Marie Daugan, Julie Erupathil, Julien Pothier, Davide Pozzi, Thierry Sifferlen, Lorenza Wyder, Isabelle Lyothier, Olivier Corminboeuf, Francois Lehembre, Imke Renz, Dominique Meyer. ACT-1002-4391 - A novel potent antagonist of the prostaglandin E2 receptors EP2 and EP4 with excellent duality [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 1809.
Abstract 1871: Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors
Authors: Cugnetti Ana Paula , Liu Haizhen , McNeeley Patricia , Wheeler Christina , Lucas Matthew , Xing Charles , Joyner Solmarie , Johnson Kyrie , Woodard Kathryn , Zhou Wei , Chang Cathy , Frey Gerhard , Boyle William J. , Short Jay M.
Published: April 2023

Human epidermal growth factor receptor 2 (HER2) is overexpressed in multiple cancers and is associated with poor prognosis. Despite the outstanding improvement in survival with the introduction of anti-HER2 therapies, therapeutic benefit is limited by many resistance mechanisms and toxicities. Clinical trials of therapeutics redirecting T cell activity to HER2+ tumors have highlighted the apparent risk of on-target, off-tumor adverse effects for this target, as HER2 is also expressed in normal epithelia. Using BioAtla’s Conditionally Active Biologic (CAB) platform, we have developed a HER2 x CAB-CD3 bispecific antibody that was engineered to bind with high affinity to the CD3 receptor and induce T cell activation under conditions that mimic the tumor microenvironment, but with reduced binding in physiological conditions. Both in vitro and in vivo efficacy data for a CAB T cell engager (TCE) targeting HER2 will be presented. Our data will demonstrate that HER2 x CAB-CD3 bispecific antibody promotes cytotoxicity of HER2+ cancer cells in vitro and induces complete regression of tumor growth in vivo. The HER2 x CAB-CD3 bispecific antibody has higher potency in inducing primary T cell activation measured by means of cytokine release and cancer cell cytotoxicity under acidic conditions compared to the non-CAB benchmark bispecific antibody. The generation of CAB bispecific antibodies with activity in the disease microenvironment minimizes on-target, off-tumor toxicities, thereby enabling higher potency-TCEs for targeting drug resistant, low expressing-HER2+ tumors. In summary, the use of CAB technology expands the universe of targets for drug development by generating a new class of potent CAB T-cell engagers with increased safety margin for potentially enhanced therapeutic indices in the clinic.

Citation Format: Ana Paula Cugnetti, Haizhen Liu, Patricia McNeeley, Christina Wheeler, Matthew Lucas, Charles Xing, Solmarie Joyner, Kyrie Johnson, Kathryn Woodard, Wei Zhou, Cathy Chang, Gerhard Frey, William J. Boyle, Jay M. Short. Novel conditionally active bispecific HER2 x CD3 T cell engager targeting solid tumors [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 1871.
Abstract 188: Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy development
Authors: Mardpour Soura , Beaurivage Claudia , Sun Jane , Jahn Lorenz , Overmeer Rene , Fielmich Lars-Eric , Hombrink Pleun , Pourfarzad Farzin , Boj Sylvia F.
Published: April 2023

Recent advances in cancer immunotherapy had a positive impact on the life expectancy of patients for a large range of clinical indications. With new treatment strategies and druggable targets being identified at an increasing pace, the number of patients eligible for cancer immunotherapy is expected to expand steadily. However, promising therapeutic developments face hurdles in translating preclinical findings into therapy since conventional 2D cancer models hold low clinical predictive value. We developed an innovative alternative, built on the discovery that adult stem cells proliferate and organise into three-dimensional organotypic structures when they are embedded into extracellular matrix. Patient specific organoids are generated from healthy and malignant tissues and stored as biobanks with high quality and reproducibility. HUB Organoids recapitulate complex characteristics of the original parental tissue, including molecular heterogeneity, and morphological and functional traits. Since cancer progression and responses to immunotherapy are governed by immune cell interactions in the tumor microenvironment, we developed an assay in which colorectal (CRC) and non-small cell lung cancer (NSCLC) tumor organoids are co-cultured with simultaneously expanded paired tumor infiltrating lymphocytes (TIL) as a source of tumor reactive cells. Our system allows robust expansion of TIL with preserved T-cell receptor repertoires and has an establishment rate of 75%. Paired resources allow for screening of immune-modulatory therapies under physiologic conditions not depending on peptide-pulsing and allo-reactivity. For this purpose, we developed a organoid-TIL co-culture system which quantifies and characterizes tumor organoid apoptosis by combining image-based analysis with flow cytometry and cytokine release assays as measurements of T-cell cytotoxicity against tumor (and normal-matched) organoids. Our system offers a powerful tool for the development and validation of cancer immunotherapy and may help to stratify cancer patients for susceptibility of various types of immunotherapies.

Citation Format: Soura Mardpour, Claudia Beaurivage, Jane Sun, Lorenz Jahn, Rene Overmeer, Lars-Eric Fielmich, Pleun Hombrink, Farzin Pourfarzad, Sylvia F. Boj. Autologous organoids and T cell co-cultures as a powerful personalized platform for immunotherapy 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 188.
Abstract 1882: SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer
Authors: Cheng Guangcun , Fu Yayuan , Zheng Hua , Li ng , He Xiaolei , Jiao Xi , Luan Shuhui , Wang Shuai , Jiang Lei , Li Wenjing , Zhang Yun , Liu Lei , Tang Renhong
Published: April 2023

Background: Although advances treatments have significantly improved the survival of patients with gastrointestinal cancer in recent decades, there is still an unmet medical need for more effective treatments. A promising strategy is the use of bispecific antibodies that recruit T cells to kill cancer cells by simultaneously binding to CD3 on T cells and tumor associated antigens. CD3-based T cell engagers are highly potent therapeutic molecules with T cell cytotoxicity activities. But high CRS risk and T cell exhaustion has been observed for high affinity CD3-based T cell engagers in clinicals. Effective and safe use of these therapeutics depends on selective targeting of cancer cells and optimal CD3 affinity. MUC17, a member of the mucin family, is a transmembrane glycoprotein only expressed on the apical membrane of normal gastrointestinal mucosal epithelial cells. MUC17 is overexpressed in 23%-52% of patients with gastric cancer. Compared to the adjacent normal tissues, the expression of MUC17 protein is consistently higher in gastric cancer tissues, suggesting that MUC17 is an attractive therapeutic target for gastric cancer.

Method & Results: We created MUC17/CD3 T cell engaging bispecific antibodies by starting with a nanobody humanized from camel and a low affinity CD3 antibody. Here we report the design and the promising preclinical activity of SCR-9171 molecule in vitro and in vivo. SCR-9171 induced T cell activation and had potent cytotoxicity of MUC17 positive tumor cells in vitro. However, the cytokine release was much lower than the positive control, which established with a high affinity CD3 antibody. Importantly, in mouse models with reconstituted human immune cells, SCR-9171 showed strong antitumor efficacy against MUC17-positive tumors through the activation of T cells. Tolerability and pharmacokinetics of MUC17/CD3 bispecific antibody are being assessed in cynomolgus monkey. The results demonstrated that SCR-9171 was well tolerated in a one-month repeat-dose toxicology study at 3mg/kg with no associated clinical signs or changes in body weight.

Conclusion: These findings suggest that MUC17/CD3 bispecific antibody is a potential therapeutic molecule for MUC17-positive solid tumor.

Citation Format: Guangcun Cheng, Yayuan Fu, Hua Zheng, ng Li, Xiaolei He, Xi Jiao, Shuhui Luan, Shuai Wang, Lei Jiang, Wenjing Li, Yun Zhang, Lei Liu, Renhong Tang. SCR-9171, a MUC17-targeted bispecific T cell engager molecule for gastrointestinal cancer [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 1882.
Abstract 1947: Clinical and genomic correlates with genetic ancestry in lung squamous cell carcinoma
Authors: Jain Sejal , Yao Alexandria G. , Allen-Gipson Diane , Momen-Heravi Fatemeh , Taylor Alison M.
Published: April 2023

Many translational studies suggest racial and ethnic survival disparities in lung squamous cell carcinoma (LSCC), with self-identified African-Americans showing significantly lower overall survival and progression-free survival than self-identified Caucasians. However, potential clinical and genomic factors contributing to this disparity have yet to be elucidated. Using clinically annotated genomic data from 501 LSCC tumor samples in the Cancer Genome Atlas (TCGA), we compared clinical data, gene expression profiles, mutations, and focal and arm-level copy number changes from tumors across ancestral groups to identify significantly differential events. Within this dataset, patients of AFR ancestry had worse survival and progression-free survival then patients of EUR ancestry. We applied the Cox Proportional Hazards model to predict overall and progression-free survival as functions of genetic ancestry alongside other genetic, molecular, and clinical variables. We found a significant difference in metastatic stage between tumors from patients of African (AFR) and European (EUR) ancestry, which was significant in predicting survival. Compared to tumors from EUR patients, tumors from AFR patients featured increased chromosome arm 8q gain and more frequent amplification of genetic locus chr8q24, which contains proto-oncogene MYC. Expression of MYC target genes was also significantly increased in AFR samples relative to EUR samples. These findings may suggest a role for the MYC pathway in differential cancer progression. We found more frequent amplification of genetic loci chr22q11 and chr16p11 in AFR samples compared to EUR samples. We identified top differentially mutated genes between groups, of which SPRR3, PDGFA, FRS3, and C21orf62 correlate with survival. We also found immune signaling gene sets enriched in the EUR group by gene set expression analysis (GSEA). These results suggest potential genetic and clinical factors implicated in racial survival disparities. Further studies and more diverse sampling of cancer patient populations are required to validate these differences and elucidate patient-specific treatment modalities.

Citation Format: Sejal Jain, Alexandria G. Yao, Diane Allen-Gipson, Fatemeh Momen-Heravi, Alison M. Taylor. Clinical and genomic correlates with genetic ancestry in lung squamous cell carcinoma [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 1947.
Abstract 1948: Novel insights into lung cancer & chronic obstructive pulmonary disease racial disparities
Authors: Thaiparambil Jose Thomas , Yin Zheng , El-Zein Randa
Published: April 2023

Introduction: Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) result from the dual effects of smoking/pollution exposure and genetic susceptibility. Blacks/African Americans (B/AA) have higher tobacco-related morbidity and mortality than Whites/European Americans (W/EA), despite smoking fewer cigarettes and starting later in life. COPD is a well-established risk factor for LC and B/AA develop COPD with less cumulative smoking and at younger ages. We will test the hypothesis that NRF2 and Focal Adhesion-PI3K-Akt-mTOR-signaling pathways play a significant role in the disparities observed between B/AA and W/EA with LC and COPD and that account for worsened outcomes in B/AA.

Methods: RNAseq analysis was conducted on tissues from 30 LC patients and 29 COPD patients undergoing lung transplantation. We compared both LC and COPD RNAseq data to identify common and unique transcripts associated with each disease.

Results: A total of 153 genes were significantly upregulated in COPD compared to LC adeno carcinoma and 174 LC squamous cell carcinoma. Ingenuity pathway analysis revealed the involvement of top regulator networks with the activation of EPSA1, CTNNB1, EP300, IKBKB and IL1B which are seen in both LC and COPD and may be involved in COPD progression to LC. We further analyzed the transcriptome of COPD between B/AA and W/EA and identified 141 significantly upregulated genes in B/AAs. We further validated our findings in TCGA B/AA LC patients to determine the extent of overlap between COPD and LC. Among these, 42 (29.8%) and 13 (9.2%) genes were significantly upregulated in TCGA LC adenocarcinoma (58 B/AA patients vs 527 from other races) and LC squamous cell carcinoma cohorts (32 B/AA patients vs 518 from other races), respectively. Survival analysis using the upregulated genes from the TCGA LC B/AA cohorts showed a higher expression of three LC adenocarcinoma (TOMM5, CEP-152 and HGS) and two LC squamous cell carcinoma specific genes (PYROXD2 and USP43) significantly associated with overall survival.

Conclusion: Our data provide novel insight on the overlap between COPD and LC and identified potential pathways that may be contributing to the significant health care disparity among B/AAs. Future studies are warranted to identify early-stage COPD markers that could be used for identification of high-risk individuals that would benefit from therapeutic interventions.

Citation Format: Jose Thomas Thaiparambil, Zheng Yin, Randa El-Zein. Novel insights into lung cancer & chronic obstructive pulmonary disease racial disparities [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 1948.
Abstract 197: Novel 3D bioprinted pancreatic tumor models for anti-cancer drug assessment
Authors: Gaikwad Shreyas Ramchandra , Srivastava Sanjay K.
Published: April 2023

The advent of bioprinting as a technology has greatly advanced the field of tissue engineering. Currently, it is being explored as a means to create complex disease models, specifically to create 3D tissue environments. Such complex models allow incorporation of dynamic microenvironments during in vitro studies. In terms of cancer drug development, the tumor microenvironment plays a significant role in cancer progression. The use of conventional 2D models in the preliminary stages of anti-cancer screening reduces the probability of successful translation towards clinical trials. In the current study, we have utilized bioprinting to create pancreatic tumor model which specifically mimics the human pancreatic tissue in terms of the biological and chemical makeup. We developed and optimized a novel bioink to create the tumor tissue. The bioink specifically mimics the pancreatic tumor microenvironment making it unique and novel as compared to the currently used bioinks which are mainly derived from animal tissues. The bioprinted tumors were then characterized for various important hallmarks of cancer such as tissue stiffness, hypoxia, and immunomodulation. We also analyzed the expression of various oncoproteins in comparison to 2D cultures to explore the role of 3D microenvironments on cancer cells. Additionally, we evaluated the efficacy of standard chemotherapies, radiotherapy and immunotherapy on the tumors as compared to 2D monolayer cultures. The bioprinted pancreatic tumors serve as a bridge between conventional assays and animal models. We observed a stark difference in the characteristics of cancer cells in monolayer cultures versus bioprinted tumors. Since a bioprinter can be programmed to control the geometry of the tissue, these models serve as the most accurate means to mimic the in vivo tumor microenvironment.

Citation Format: Shreyas Ramchandra Gaikwad, Sanjay K. Srivastava. Novel 3D bioprinted pancreatic tumor models for anti-cancer drug assessment [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 197.
Abstract 1971: Understanding the perspectives of Latino smokers on physical activity: A qualitative study
Authors: Cartujano-Barrera Francisco , Alaniz-Cantu Edgar , Rojas Maria Valeria Bautista , Hernández-Torres Ruthmarie , McIntosh Scott , Ossip Deborah J. , Cupertino Ana Paula
Published: April 2023

Introduction: Smoking and sedentarism frequently co-occur among Latinos. Evidence suggests that moderate to vigorous physical activity (MVPA) may enhance smoking cessation rates. However, this synergistic phenomenon has not been studied among Latinos, the largest minority group in the U.S.

Objective: To understand the perspectives of Latino smokers on physical activity.

Methods: Participants were recruited using community-based recruitment strategies. Semi-structured interviews were conducted in English and Spanish with Latino smokers. The Health Belief Model was used as a framework for qualitative theoretical analysis.

Results: At baseline, participants’ mean age was 54.9 years old (SD 12.1), 50% of the participants were female, and 85% self-identified as heterosexual or straight. Eight participants (40%) indicated their language of preference as “Only Spanish” and 50% were born in Cuba and the Dominican Republic (25% for each country). Most participants (70%) were light smokers (1-10 cigarettes per day), 35% smoked their first cigarettes within five minutes after waking up, and 50% used menthol cigarettes. We identified perceived benefits (e.g., mood management, weight loss, strategy to quit smoking), susceptibility (e.g., risk of cardiovascular diseases and physical impairment, susceptibility to weight gain), and barriers (e.g., lack of social support, health constraints, and low financial resources) of being physically active. Moreover, we identified cues to action to do physical activity (e.g., being a role model: “⋯I’m going to do it [physical activity] so she [the daughter] can do it too⋯”; spending time with family and friends: “Well, since I have some little nephews and some little nieces... I go with them to the playground⋯”; being outdoors: “⋯go to the parks a lot or go nature walking⋯ being out in the woods⋯ taking all of nature⋯ I would go down to [local towns in New York] on my bicycle⋯”).

Conclusion: Multiple perceived factors of being physically active were identified among Latino smokers. These factors provide concrete operational strategies to address smoking cessation and physical activity among Latinos. Further research is needed on how best to integrate these perspectives into smoking cessation interventions.

Citation Format: Francisco Cartujano-Barrera, Edgar Alaniz-Cantu, Maria Valeria Bautista Rojas, Ruthmarie Hernández-Torres, Scott McIntosh, Deborah J. Ossip, Ana Paula Cupertino. Understanding the perspectives of Latino smokers on physical activity: A qualitative 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 1971.
Abstract 2085: Structural principles of kinase-selectivity drug design
Authors: Zhang Mingzhen , Liu Yonglan , Jang Hyunbum , Nussinov Ruth
Published: April 2023

Kinase drug selectivity is one of the main challenges in cancer research. The kinases encoded byhuman genome share the highly similar catalytic kinase domains. As a result, the drug that isdesigned to target one kinase frequently binds to another, leading to the off-target toxicity. Despitethe high structural similarity, the kinase drug pockets at the atomic level are not completelyidentical. We ask that whether there are some inhibitor-accessible geometric features in the kinasepockets that only exist in one kinase but not in all others. To target these unique features in thekinase pockets may help design the kinase drugs with the kinome-wide selectivity. In this work,we describe a transformation invariant protocol (binary network with unsupervised clustering) andperform the kinome-wide structural bioinformatic analysis by integrating the experimental andartificial intelligence (AI)-based kinase structures. The results show that ~ 66.8 % kinases containthe unique features that may distinguish them from all others and the geometric features shared byless than seven other kinases can be found in all the analyzed kinases. We apply the binary networkto EGFR tyrosine kinase and AKT1 serine/threonine kinases, illustrating the potential structuralstrategies to design the high-selectivity kinase drugs. Finally, we develop a cross-platformsoftware, named as KDS (Kinase Drug Selectivity), to achieve the customized real-timevisualization and mutation analysis of the binary networks in the human kinome.

Citation Format: Mingzhen Zhang, Yonglan Liu, Hyunbum Jang, Ruth Nussinov. Structural principles of kinase-selectivity drug design [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 2085.
Abstract 2154: Differential expression of the PI3K-Akt signaling pathway pre and post chemotherapy in relation to hormonal profile in African women
Authors: Kengni Hurette Junie Chansi
Published: April 2023

Background: Breast cancer (BC) is the most common cancer in US and Canadian women. Despite therapeutic advances, it remains the second leading cause of female cancer mortality. Aggressive breast cancers are represented as a clinical (inflammatory BC or locally advanced BC) or as a biopathological form (triple negative BC or HER2+ BC). These aggressive forms have a poor prognosis. In the US, African Americans have a 41% higher BC death rate than Caucasians women. As observed in the US, in African Gabon women, a more aggressive and cases of triple negative BC are found. Aggressive BC are mainly associated with African women. At this stage, chemotherapy is the main therapeutic treatment but chemoresistance is the major hurdle. One solution to chemoresistance would be to found candidates biomarkers that predict therapeutic responses. The goal of our study was to establish an RNA signature that could differentiate chemosensitive from chemoresistant patients in BC African women.

Methods: RNA sequencing technique was used to establish expression profiling in African women before and after chemotherapy using three groups of aggressive BC patients treated with: Doxorubicin, 5-Fluorouracil or Navelbine. We first isolated RNA from tissues fixed in paraffin and sequenced it via the Nextseq 2000 system. A tximport (v1.20.0) and DESeq2 (v1.26.0) analysis then identified significantly and differentially expressed transcripts between the different groups.

Results: In the doxorubicin group, post-chemotherapy patients had 962 significant genes out of the 46461 transcripts compared to pre-chemotherapy patients. The post-chemotherapy 5-FluoroUracil group had 3723 significant genes out of 43821 transcripts compared to pre-chemotherapy Fluorouracil group and the post-chemotherapy Navelbine group had 980 significant genes out of 44689 transcripts compared to pre-chemotherapy Navelbine group. Relevant overexpressed genes were selected for validation by immunohistochemistry

(IHC). We found an enrichment in the KEGG and PI-3K/Akt pathways and observed that Akt downstream substrates were express differently between pre- and post-chemotherapy patients.

Conclusion: Our study suggests that some of the overexpressed post chemotherapy genes could serve as biomarkers of aggressive BC. This is the first study in Canada to investigate Doxorubicin, Flurouracile and Navelbine chemoresistance-related genes in African women and could lead to the discovery of diagnostic markers and therapeutic targets.

Citation Format: Hurette Junie Chansi Kengni. Differential expression of the PI3K-Akt signaling pathway pre and post chemotherapy in relation to hormonal profile in African women [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 2154.
Abstract 2169: NAD(P)H: quinone oxidoreductase 1 (NQO1)- A viable biomarker in colorectal cancer
Authors: Ganji Chaithanya , Lakkakula Bhaskar VK , Behera Santosh Kumar , El-Rayes Bassel F.
Published: April 2023

Background/Objective: Colorectal cancer (CRC) is aggressive and widespread (3rd among malignancies) in the United States. NAD(P)H: Quinone Oxidoreductase 1 (NQO1) is an enzyme that contributes to chemoprotection for CRC. The aim of this meta-analysis is to test the connection between NQO1 C609T polymorphisms and CRC risk. Furthermore, the study explores the binding capacity and efficacy of BBI 608 against NQO1 in CRC through molecular docking. The inhibitor will then be tested in vitro.

Methods: PubMed, Web of Science, and Google Scholar were used in bibliographic searches. For the NQO1 C609T analysis, a total of 18 studies were used. Data was gathered and subsequently calculated using the pooled odds ratio (OR) (95% confidence interval, CI). Molecular docking, Western Blot and QRT-PCR were used to determine the molecular function of BBI 608 and NQO1.

Results: The relation between NQO1 polymorphism and CRC risk (TT + CT vs. CC: OR=1.19, 95% CI =1.06-1.34, p<0.001) was significant. Furthermore, stratified investigation based on ethnicity indicated significant association between NQO1 polymorphism and CRC risk (TT + CT vs. CC: OR=1.17, 95% CI =1.08-1.27, p<0.001). This study indicates that the C609T polymorphism of NQO1 is linked with CRC risk in Asians and Caucasians. To observe the molecular properties of BBI 608 (NQO1 inhibitor) and to analyze the exact mechanism of NQO1 on CRC, computational approaches were applied. This investigation provides a detailed understanding of the interaction between NQO1 and BBI 608 and its implication in CRC therapy. To support this computational analysis, in vitro studies were performed. BBI 608 creates higher cytotoxicity in a dose dependent manner in CRC cell lines. BBI 608 treatment significantly (p<0.001) reduced the NQO1 expression at protein and messenger levels in both CRC (HCT 116 and RKO) cell lines.

Conclusion: Based on meta-analysis and computational approach, NQO1 is a viable biomarker and targeted molecule in CRC. In vitro results showed that inhibiting NQO1 with the drug BBI 608 decreased cell proliferation in both CRC cell lines. Knockout or overexpression or site directed mutagenesis is essential for a better understanding about BBI 608 targeted NQO1 and its amino acids.

Citation Format: Chaithanya Ganji, Bhaskar VK Lakkakula, Santosh Kumar Behera, Bassel F. El-Rayes. NAD(P)H: quinone oxidoreductase 1 (NQO1)- A viable biomarker in colorectal cancer [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 2169.
Abstract 2243: Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma
Authors: Chen Pie-Che , Lin Guan-Ling , Lin Hon-Yi , Huang Wan-Hong , Chuang Yu-Ming , Lin Ru-Inn , Wu Shu-Fen , Shen Cheng-Huang , Chan Michael W.Y.
Published: April 2023

Urothelial carcinoma (UC) is the second most common malignancy of the urinary system with high rate of recurrence, UC patients therefore needed to be treated with surgery followed by chemotherapy. Development of novel therapeutics with minimal side-effect is an urgent issue. Our previous study showed that cyproheptadine (CPH), an anti-histamine, exhibited antitumor activity in UC in vitro and in an xenograft model. In this study, we performed RNA-Seq to examine genes that are differentially expressed after treatment with CPH in UC cells. Our result showed that several genes, including IRF6, were upregulated after treatment with CPH in BFTC905 UC cells. Further experiments found that treatment of CPH could restore the expression of IRF6 in several other UC cell lines, which is due to promoter hypomethylation and enrichment of H3K27 acetylation, as well as H3K4 mono-methylation. Importantly, treatment of CPH can inhibit tumor growth in a syngeneic mouse tumor model. The tumor growth can be further inhibited by combination treatment of CPH and immune checkpoint blockade. Flow cytometric analysis of the tumor found that NK cells are significantly enriched in the CPH treatment group, as compared to DMSO control. Co-culture experiments confirmed that UC cells pretreated with CPH showed an increased NK-92-mediated cytotoxicity. In conclusion, these results suggested that treatment of CPH can inhibit tumor growth, by epigenetic priming of IRF6 in UC. The role of CPH in eliciting anti-tumor innate immune response deserves further investigation.

Citation Format: Pie-Che Chen, Guan-Ling Lin, Hon-Yi Lin, Wan-Hong Huang, Yu-Ming Chuang, Ru-Inn Lin, Shu-Fen Wu, Cheng-Huang Shen, Michael W.Y. Chan. Cyproheptadine exhibits anti-tumor activity by reversing the epigenetic silencing of IRF6 in urothelial carcinoma [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 2243.