bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 3952: Preclinical anti-tumor effects of MDM4/MDMX inhibitor XI-006 in breast cancer and prostate cancer cell lines mediated through reduced tumor cell migration
Authors: Cruz Arielle De La , George Andrew , Cruz Payton De La , Pinho-Schwermann Maximilian P. , Meza Kimberly S. , Arnoff Taylor , Sahin Ilyas , Graff Stephanie L. , Carneiro Benedito A. , El-Deiry Wafik S.
Published: April 2023

MDM2 and MDM4/MDMX have emerged as potential mediators of tumor progression, organ-specific metastasis, and hyper-progression after immune checkpoint blockade therapy. While there are currently a number of MDM2 inhibitors in clinical trials, we found no pure MDM4/MDMX inhibitors under clinical investigation. Because hormone-resistant cancers pose a significant challenge for clinical intervention, the identification of translatable novel therapeutic targets remains an important goal. Analysis of triple-negative breast cancer (TNBC) and castration-resistant prostate cancer (CRPC) reveals overexpression of p53 negative regulator MDM4/MDMX as a frequent alteration in these cancers. There is an urgent need to study and target MDM4/MDMX in cancer therapy and this may ultimately include dual MDM2 and MDM4/MDMX inhibitors. However, it is clear that MDM4/MDMX is a primary oncogenic driver that requires specific therapeutic targeting. As metastasis is often observed clinically in patients diagnosed with breast and prostate cancer, we sought to expand our understanding of the metastasis reduction potential of a previously described preclinical MDM4/MDMX inhibitor, a 4-nitrobenzofuroxan derivative, XI-006 (NSC207895). In a scratch assay using breast and prostate cancer cell lines, increasing doses of XI-006 decreased tumor cell migration in a time and dose-dependent manner, demonstrating the benefit of MDMX inhibition in preventing the induction of tumor cell migration. The exact mechanism of this result remains unclear, and further investigation is needed to elucidate the impact of XI-006 on TNBC and CRPC cell proliferation and migration. Our future directions include identifying the synergistic potential of combining MDM4/MDMX inhibitor XI-006 with other cancer therapies, assessing the impact of XI-006 on immune responses in co-culture studies, and testing therapeutic efficacy in vivo.

Citation Format: Arielle De La Cruz, Andrew George, Payton De La Cruz, Maximilian P. Pinho-Schwermann, Kimberly S. Meza, Taylor Arnoff, Ilyas Sahin, Stephanie L. Graff, Benedito A. Carneiro, Wafik S. El-Deiry. Preclinical anti-tumor effects of MDM4/MDMX inhibitor XI-006 in breast cancer and prostate cancer cell lines mediated through reduced tumor cell migration. [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 3952.
Abstract 3982: Anti-Stanniocalcin 1 antibody as a potential therapeutic strategy for liver fibrosis and hepatocellular carcinoma
Authors: Suen Alfred Long-Hin , Chan Kristy Kwan-Shuen , Lo Regina Cheuk-Lam
Published: April 2023

Introduction: Hepatocellular carcinoma (HCC) is the sixth most frequently diagnosed cancer and the third leading cause of cancer deaths. Liver fibrosis (LF) is a progressive disease and cirrhosis, the advanced stage of LF, is per se a risk factor for HCC. Moreover, LF persists after the development of HCC. Stanniocalcin 1 (STC1), as a serum biomarker of both HCC and LF as we previously reported, was found to be secreted from HCC cells and hepatic stellate cells (HSCs). STC1 promoted cell migration and invasion of HCC and activation of HSCs, suggesting that STC1 could be an actionable target of both diseases. As a secretory protein, STC1 could potentially be targeted by an antibody approach.

Objectives: This study aims to investigate the therapeutic values of targeting secretory STC1 in HCC and LF models using antibody approach, including in the interplay between HSCs and HCC cells.

Methods: Human anti-STC1 antibody was harvested and purified from a hybridoma cell line of a designed epitope. In vitro transwell migration and invasion assays were performed on human HCC cell lines. Co-culture assays were set up with HCC cells cultured in conditioned medium (CM) collected from LX2, a human HSC cell line. Expression of fibrogenic markers were measured by western blotting, qPCR and ELISA.

Results: Enforcement of STC1, either by viral transfection of STC1-overexpressing vector or by the treatment of recombinant STC1 protein, increased the migration and invasion of HCC cells. The effects were abrogated by the co-treatment of anti-STC1 antibody. The enhanced migratory and invasive abilities of HCC cells induced by activated HSC CM were abolished by anti-STC1 antibody. In addition, anti-STC1 antibody suppressed the secretion of type I collagen (COL1) and the intracellular expression of fibrogenic markers alpha-smooth muscle actin (ɑSMA) and TIMP metallopeptidase inhibitor 1 (TIMP1) in TGFβ1-activated HSCs.

Conclusion: Anti-STC1 antibody displays therapeutic effects on HCC in vitro. It is also shown to suppress the expression of fibrogenic markers in activated HSCs. Anti-STC1 antibody is a potential therapeutic strategy for both HCC and LF.

Citation Format: Alfred Long-Hin Suen, Kristy Kwan-Shuen Chan, Regina Cheuk-Lam Lo. Anti-Stanniocalcin 1 antibody as a potential therapeutic strategy for liver fibrosis and hepatocellular 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 3982.
Abstract 4062: The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy
Authors: Liu Yarong , Sun Jingwei , Sheng Yao , Wang Jingman , Jin Jiahui , Li Fei , Chen Lingyun , Zhou Di , Tan Yongchao , Wang Quanwei , Xu Zhao , Li Haibao , Wang Pin , Cui Jun
Published: April 2023

Adoptive cell therapy by tumor-infiltrating lymphocytes (TILs) has demonstrated promising therapeutic effects in multiple types of solid tumors and significantly prolonged the survival of late-stage patients. However, the “prone-to-exhaustion” phenotype of the final TIL product after rapid expansion during manufacture and the presence of various immunosuppressive mechanisms in tumor microenvironment (TME) compromises the persistence and anti-tumor efficacy of TIL post infusion. To discover potential immunoregulatory targets that could maximize the function of TIL, we established a genome-wide CRISPR/Cas9 screening platform, ImmuT Finder®, to unbiasedly identify functional gene targets in primary T cells. Notably, this platform employed T cells bearing a tumor-antigen specific TCR-T that were repeatedly stimulated by tumor cells with cognate tumor antigen and demonstrated similar exhaustion profile as TIL. We selected top 30 targets after several rounds of screening and quickly validated their function in a 96-well array. Then, the top targets that showed significantly enhancement in proliferation and function of TCR-T were further selected, and their combinational effects on TIL were tested both in vitro and in vivo. Finally, double KO of GT304 and GT312 (GT316) stands out as the most potent combination, which significantly improves TIL proliferation and cytokine release, eradicates tumor growth in both CDX and PDX mouse models and promotes long-term in vivo persistence with low-dependence on IL-2. Specific and potent sgRNAs targeting both targets have been selected, and manufacturing process of GT316 TIL product has been developed (KOReTIL®). In summary, these data demonstrated that our ImmuT Finder® platform enables unbiased discovery of potent and novel targets for the development of T cell therapy and support the clinical assessment of GT316 as a next-generation TIL therapy. Currently, an investigator-initiated trial of GT316 is ongoing in China.

Citation Format: Yarong Liu, Jingwei Sun, Yao Sheng, Jingman Wang, Jiahui Jin, Fei Li, Lingyun Chen, Di Zhou, Yongchao Tan, Quanwei Wang, Zhao Xu, Haibao Li, Pin Wang, Jun Cui. The discovery and development of a CRISPR/Cas9-engineered tumor-infiltrating lymphocytes product (GT316) as a next-generation TIL therapy. [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 4062.
Abstract 4103: The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Authors: Li Nan , Quan Alex , Li Dan , Ren Hua , Ni Weiming , Zhou Jing , Cachau Raul , Ho Mitchell
Published: April 2023

Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we developed CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4) based-CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We found that a structurally rigid IgG4H and CD28TM domain making the two D4 fragments in proximity drove CAR dimerization, which led to enhanced T cell signaling and tumor regression in orthotopic pancreatic cancer models with low antigen density. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR-T cells revealed specific genes (e.g., ID1) associated with high T cell polyfunctionality. This study demonstrates the potential of VHH-based CAR-T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.

Citation Format: Nan Li, Alex Quan, Dan Li, Hua Ren, Weiming Ni, Jing Zhou, Raul Cachau, Mitchell Ho. The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic 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 4103.
Abstract 4104: Development of adoptive T-cell therapies to target heterogeneity of mCRPC
Authors: Lopez Lupita S. , Bangayan Nathanael , Witte Owen , Priceman Saul J.
Published: April 2023

Metastatic castration resistant prostate cancer (mCRPC) remains a significant challenge with limited durable therapeutic responses, and innovative and effective treatment strategies are needed. Advanced mCRPC often comprises a heterogeneous population of prostate adenocarcinoma (PrAd) and neuroendocrine prostate cancer (NEPC), and current targeted therapies often result in transient anti-tumor responses. Chimeric antigen receptor (CAR) T-cell therapies are being actively investigated to target mCRPC, including CARs targeting antigens that are overexpressed in PrAd. Our group has developed a CAR T cell targeting the PrAd antigen, prostate stem cell antigen (PSCA), and have an ongoing phase 1 trial at City of Hope in patients with mCRPC. However, we anticipate that targeting NEPC in addition to PrAd will be required to achieve durable anti-tumor responses in patients. Here, we have developed novel dual-targeting approaches for the simultaneous treatment of both PrAd and NEPC. Our first approach optimizes a tandem CAR T-cell approach capable of targeting distinct antigens found on both PrAd and NEPC. Additionally, we are actively developing combinations of PSCA-CAR T-cells with secretable T-cell bispecific antibodies to target NEPC antigens. Our studies encompass the in vitro and in vivo safety and efficacy of CAR T-cells engineered to co-target PrAd and NEPC for the treatment of heterogeneous mCRPC.

Citation Format: Lupita S. Lopez, Nathanael Bangayan, Owen Witte, Saul J. Priceman. Development of adoptive T-cell therapies to target heterogeneity of mCRPC. [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 4104.
Abstract 4180: Knowledge and barriers to colorectal cancer screenings in people experiencing homelessness in Central Florida
Authors: Sankar Harini , Odahowski Cassie L.
Published: April 2023

Purpose of the study: The purpose of this study is to assess how existing knowledge about colorectal cancer screenings and access to resources affect the ability to obtain colorectal cancer screening in people experiencing homelessness in Central Florida.

Procedures: A team of researchers from the University of Central Florida will survey subjects who do not have stable housing in two Central Florida locations: a local shelter for men, women, and children and a resource center for the unsheltered. The survey will take place in February 2023 with a sample size goal of 400. The survey will assess current understanding of CRC screenings and available/lacking resources necessary for completing CRC screening in this population. Our inclusion criteria include those who are undomiciled, age 45 and over who speak Spanish or English.

Preliminary Results: Anticipated results from previous work by our research team with this population indicate that we will have a large, diverse study sample. The results will include demographic data, frequency of insurance coverage, type of insurance coverage, knowledge of CRC screening recommendations, concerns related to CRC, rate of past completed screening, and perceived barriers to accessing CRC screening.

Conclusions: This study will be the first to examine this research topic in Florida. The results will identify the knowledge of CRC screening recommendations, barriers to CRC screening and identify resources needed for the unhoused population to achieve CRC screening in the future.

Citation Format: Harini Sankar, Cassie L. Odahowski. Knowledge and barriers to colorectal cancer screenings in people experiencing homelessness in Central Florida. [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 4180.
Abstract 419: Elevated Akt/mTOR signaling drives therapy resistance in ALM
Authors: Narula Jeremy A. Bravo , Rebecca Vito W.
Published: April 2023

Metastatic acral lentiginous melanoma (ALM) is the most lethal subtype of cutaneous melanoma and effective therapies for patients have not been established. Studies revealed a link between the dysregulation of CDK4/6 and ALM mortality, however CDK4/6 inhibitors (CDK4i/6i) have proved ineffective in patients with advanced ALM. The tumor suppressor Rb was recently shown to have a novel suppressive role towards mTORC2. Here, we elucidate the role of a non-canonical tumor suppressor function of Rb in negative regulation of mTOR in CDK4i/6i-resistance. We hypothesize that the loss of Rb induced by CDK4i/6i triggers phosphorylation of Akt and downstream mTORC1 signaling pathways. We characterized baseline activity of the PI3K/AKT/mTOR pathway in a panel of ALM cell lines, finding heterogeneity across signaling. We immunoblotted for key proteins involved in the signal reprogramming hypothesized: pRb, pAkt, pS6 to define activation status and found the loss of Rb phosphorylation preceded the enrichment of pAKT, supporting the non-canonical role of Rb tumor suppression and the Rb-mTORC2 signaling axis as intrinsic CDK4i/6i mechanism. In parallel, we assessed the essential protein-protein interactions required for mechanistic mTORC1 activation—mTOR and Rheb GTPase. The enrichment of these interactions shortly after introducing CDK4i/6i supported our hypothesized mechanism. Translational utility of CDK4i/6i and mTORi dual inhibition was determined via long-term Colony Formation Assays (CFAs) using Palbociclib, rapamycin and sapanisertib (TAK228), a catalytic mTOR inhibitor. We generated Palbociclib (acquired)-resistant ALM cell lines and investigated the pharmacological inhibition of PI3K signaling pathways through immunoblot and colony-formation assays. Concurrent mTORi and CDK4i/6i inhibition showed effective reduction in pRb, pS6, Cyclin D and increases in Cleaved PARP protein, suggesting apoptotic cell death was elevated with combined CDK4i/6i+mTORi treatment. Similarly, CFAs revealed dual inhibition elicited superior antiproliferative effect over the monotherapy treatments. CFAs with acquired-resistance cell lines also showed that combination inhibition decreased colony formation, showing the potential utility of concurrent CDK4i/6i and mTORi as an approach against acquired resistance. Our results show the efficacy of combined inhibition as an anti-tumor strategy.

Citation Format: Jeremy A. Bravo Narula, Vito W. Rebecca. Elevated Akt/mTOR signaling drives therapy resistance in ALM [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 419.
Abstract 4245: Effects of black raspberries extract on DNA repair capacity and metabolic activation/detoxification of the tobacco carcinogen dibenzo[def,p] in human oral cells
Authors: Sun Yuan-Wan , Chen Kun-Ming , Sales Ana H. , Geacintov Nicholas , El-Bayoumy Karam
Published: April 2023

We previously reported that black raspberries (BRB) powder inhibits dibenzo[def,p]chrysene (also known as dibenzo[a,l]pyrene; DBP)-induced DNA damage, mutagenesis and carcinogenesis in the mouse oral cavity. The effects of BRB on the capacity of DNA repair was investigated in an established in vitro system using HeLa cells to assess the DNA repair capacity. We found that pre-treatment of Hela cells with BRB extracts (BRBE) can enhance the nucleotide excision repair (NER) of a bulky DNA adduct derived from the tobacco oral carcinogen benzo[a]pyrene by ~24% and this effect is correlated with the enhanced expressions of NER factors XPA and XPB. The NER activity of guanidinohydantoin (Gh), an oxidatively-derived non-bulky DNA lesion, is also enhanced by ~24%, while its base excision repair activity is enhanced by only ~6%. Using human oral leukoplakia (MSK-Leuk1) and oral squamous cell carcinoma SCC1483, we demonstrated that BRBE can inhibit DNA damage induced by DBP through the induction of GSH synthesis and enhancing GSH conjugates thereby inhibiting DNA damage. The effects of BRBE in MSK-Leuk1 and SCC1483 cells were further investigated on the DNA excision repair protein ERCC1 at 1, 6 and 24 h. ERCC1 forms the ERCC1-XPF enzyme complex that participates in several DNA repair pathways. Western blot analyses revealed that BRBE induced higher ERCC1 expression in SCC1483 than those observed in MSK-Leuk1 cells in a time-dependent manner. The results of our study demonstrate that BRBE is capable of inhibiting the metabolic activation, enhancing the detoxification pathway and DNA repair capacity which are consistent with its chemopreventive activity in vivo. Supported by NIH grant #CA173465.

Citation Format: Yuan-Wan Sun, Kun-Ming Chen, Ana H. Sales, Nicholas Geacintov, Karam El-Bayoumy. Effects of black raspberries extract on DNA repair capacity and metabolic activation/detoxification of the tobacco carcinogen dibenzo[def,p] in human oral 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 4245.
Abstract 4283: scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model
Authors: Liu Yuqian , Chen Yan , Wu Huanwen , Zhang Xuanping , Lai Xin , Yi Xin , Liang Zhiyong , Wang Jiayin
Published: April 2023

Microsatellite instability (MSI) is an important genomic biomarker for cancer diagnosis and treatment. For some cancers with high-degree of heterogeneity, e.g. endometrial cancer, the existing approaches always fail to identify the micro-satellite instability on one or multiple sub-clones, which would deprive the chance for patients to benefit from treatments. However, it is a computational challenge to estimate the sub-clonal MSI because multiple sub-clones may share the genomic status. Herein, in this paper, we propose an accurate and efficient algorithm, named scMSI, to estimate the sub-clonal microsatellite status. scMSI adopts an alternating iterative model to de-convolute the length distribution, which is a mixture of sub-clones. During the deconvolution, an optimized division of each sub-clone is achieved by a heuristic algorithm, which is bounded to the clonal proportions best consistent with the known clonal structure. To evaluate the performance, we conducted a series of experiments on simulation datasets. The results supported that scMSI solved the detection problem of MSI on sub-clones. It outperforms the existing approaches on multiple metrics. In addition, we collected a cohort of 16 endometrial cancer patients, who have positive responses on the treatment but with negative MSI status. We sequenced these patients. scMSI reported MSI on sub-clones according the sequencing data, which are further validated by the conclusions on immunohistochemistry. Thus, scMSI could provide a powerful tool for MSI analysis.

Citation Format: Yuqian Liu, Yan Chen, Huanwen Wu, Xuanping Zhang, Xin Lai, Xin Yi, Zhiyong Liang, Jiayin Wang. scMSI: Accurately detect the sub-clonal micro-satellite instability by an integrative Bayesian model. [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 4283.
Abstract 4365: Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients
Authors: Mosha Maua , Mayer Jennifer , Amankwah Ernest K.
Published: April 2023

The influence of comorbidities at index diagnosis on outcomes of pediatric leukemia and lymphoma is not well established. We evaluated the association between medical comorbidities and pediatric acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LL) outcomes in a retrospective cohort study using electronic health records from the TriNetX Research Network Database, a global de-identified federated health research network. Study participants included pediatric (≤21 years) patients newly diagnosed with ALL or LL from July 2009-June 2019 and followed through June 2022. The main outcomes included progression/relapse, toxicity, overall mortality and cancer-specific mortality. Comorbidities included chronic lung disease; congenital heart disease; neurologic, immune, hematologic, vascular and genetic disorders; renal disease; gastrointestinal disease; prematurity and hepatobiliary disease. Patients with any comorbidity were matched with patients with no comorbidity on age at diagnosis, gender, race/ethnicity, and treatment using propensity score matching. We identified 5,375 patients diagnosed with ALL/LL with comorbidities and 5,375 without comorbidities after propensity score matching. The mean age at diagnosis was 9.7 years (standard deviation=6.2). A higher proportion of the patients were male (56.9%), White (63.6%) and Not Hispanic or Latino (63.4%). Patients diagnosed with comorbidities had a higher risk for progression/relapse (73% vs 51%; Relative Risk, RR=1.42, 95% confidence interval (CI)=1.38-1.47) and treatment related toxicity (80% vs 50%; RR=1.59, 95% CI=1.54-1.64), compared to patients diagnosed with no comorbidities. Similarly, overall mortality (Hazard ratio, HR=1.62, 95% CI=1.37-1.91) and cancer-specific mortality (HR=4.39, 95% CI=2.28-8.46) were higher among patients diagnosed with comorbidities than those without comorbidities. Comorbidities among patients diagnosed with ALL/LL is associated with poor outcomes independent of treatment and thus targeted interventions for the proper management of these patients are needed to improve outcomes.

Citation Format: Maua Mosha, Jennifer Mayer, Ernest K. Amankwah. Comorbidities at diagnosis are associated with poor outcomes among pediatric acute lymphoblastic leukemia and lymphoblastic lymphoma patients. [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 4365.
Abstract 4372: Hierarchy of prognostic quality markers after curative-intent resection of stage IA non-small cell lung cancer
Authors: Shao Huibo , Lee Yu-Sheng , Fehnel Carrie , Akinbobola Olawale , Saulsberry Andrea , Dortch Kourtney , Matthews Anberitha T. , Faris Nicholas R. , Ray Meredith A. , Smeltzer Matthew , Osarogiagbon Raymond U.
Published: April 2023

Introduction. 5-year disease-free survival after curative-intent resection of stage IA NSCLC approximates 65%. The quality of resection and differences in cancer biology probably account for most curative-intent treatment failure. We evaluated the hazard associated with markers of surgical quality.

Methods. Using the population-based Mid-South Quality of Surgical Resection cohort, we compared outcomes of pathologic IA NSCLC resections from 2009 to 2021. With the stringent International Association for the Study of Lung Cancer complete (R0) resection for reference, we evaluated eight quality benchmarks: wedge resection; resections with positive margins; non-examination of lymph nodes (LN) from anywhere (pNX), mediastinal (pNXmed), intrapulmonary, hilar, low paratracheal and subcarinal stations. We evaluated hazard ratios (HR), adjusted for age, sex, insurance, histology, comorbidity, preoperative staging and technique of resection (95% CI) from Proportional Hazards models.

Results. Of 2,243 resections, 906 (41%) were R0; 1,333 were non-R0, including 3% R1/R2, 13% pNX, 15% wedge resections, 15% pNXmed, 45% without subcarinal, 41% without hilar, 47% without low paratracheal, and 36% without intrapulmonary LNs.Compared to IASLC-R0, adjusted HRs were: 2.04 (1.21-3.44) for R1/R2; 1.75 (1.33-2.31) for pNX; 1.64 (1.26-2.14) for wedge resections; 1.35 (1.12-1.63) for non-examination of intrapulmonary LN; 1.33 (1.03-1.72), pNXmed; 1.25 (1.02-1.53), non-examination of hilar LN; 1.15 (0.95 - 1.39) missing station 4; and 1.11 (0.90-1.37) missing station 7 LNs.

Conclusion. Surgical quality, indicated by markers of LN evaluation, have significant impact on long-term survival and should be required selection criteria or stratification factors in lung cancer surgery trials.

Citation Format: Huibo Shao, Yu-Sheng Lee, Carrie Fehnel, Olawale Akinbobola, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Meredith A. Ray, Matthew Smeltzer, Raymond U. Osarogiagbon. Hierarchy of prognostic quality markers after curative-intent resection of stage IA non-small cell lung 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 4372.
Abstract 4382: Evolution of curative-intent lung cancer surgery in a 4 eras in the population-based mid-south quality of surgical resection (MS-QSR) cohort
Authors: Akinbobola Olawale , Ray Meredith A. , Fehnel Carrie , Saulsberry Andrea , Dortch Kourtney , Matthews Anberitha T. , Faris Nicholas R. , Godfrey Caroline M. , Smeltzer Matthew , Osarogiagbon Raymond U.
Published: April 2023

Background. Most patients die within 5 years of curative-intent lung cancer surgery

Differences in surgical quality and cancer biology drive long-term overall survival (OS) differences after curative-intent resection. From 2009 onward, we implemented a sequence of interventions to improve surgical quality and pathologic evaluation in a regional population. We evaluated population-level surgical quality and OS in the MS-QSR cohort.

Methods. We categorized the MS-QSR into 4 (approximately) 5-year eras: 1) 2004-08, baseline; 2) 2009-13 (quality feedback and pilot intervention studies); 3) 2014-18 (surgical intervention with a lymph node collection kit); 4) 2019-22 (dual surgical and pathology intervention with novel gross dissection method). We compared surgical quality and OS across eras using standard statistical methods.

Results. Of 6,701 resections, 15%, 33%, 32%, and 20% were in Eras 1-4, respectively. American College of Surgeons Operative Standard 5.8 quality was attained in 4%, 22%, 45%, and 65% of resections in Eras 1-4, respectively; the International Association for the Study of Lung Cancer’s stringent definition of ‘complete resection’ was achieved in 0%, 9%, 20%, and 31%, respectively; 120-Day mortality rates were 10%, 9%, 7%, and 4%; 3-year OS rates were 49%, 64%, 71%, and 84%; 5-year OS, 34%, 52%, and 61%, in Eras 1-3 (too early for Era 4); p<0.0001 for all comparisons.

Conclusion. Population-level surgical quality and OS have improved sequentially in parallel with implementation of interventions to surgical and pathology practices. The higher OS threshold in the MS-QSR creates a platform to interrogate the biologic drivers of surgical outcomes differences.

Citation Format: Olawale Akinbobola, Meredith A. Ray, Carrie Fehnel, Andrea Saulsberry, Kourtney Dortch, Anberitha T. Matthews, Nicholas R. Faris, Caroline M. Godfrey, Matthew Smeltzer, Raymond U. Osarogiagbon. Evolution of curative-intent lung cancer surgery in a 4 eras in the population-based mid-south quality of surgical resection (MS-QSR) cohort. [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 4382.
Abstract 4448: Chemokine (C-X-C motif) ligand 17 promotes cutaneous squamous cell carcinoma via modulating tumor-immune evasion
Authors: Khandelwal Alok R. , Kandula Rema Anisha , Daniel Emily , Alam Md Maksudul , Craighead Henry , Moore-Medlin Tara , Nathan Cherie-Ann O.
Published: April 2023

Cutaneous squamous cell carcinoma (cSCC) is a keratinocyte-derived invasive and metastatic tumor of the skin. It is the second-most commonly diagnosed form of skin cancer, striking 200,000 Americans annually. Further, organ transplant patients are at significantly increased risk of cSCC compared to the general population. Excision of cSCC of the head and neck area results in significant facial disfigurement. An increased understanding of the mechanisms involved in the pathogenesis of cSCC could identify means to prevent, inhibit, and reverse this process. Chemokine (C-X-C motif) ligand 17 (CXCL17) is the latest chemokine family member, and an increased CXCL17 protein expression was observed in both mouse and human cSCC cell lines. Further, deletion of CXCL17 was associated with significant inhibition of tumor cell-intrinsic properties such as proliferation, migration, and motility. CXCL17 is identified as a potent chemoattractant for macrophages, dendritic cells and myeloid-derived suppressive cells. Accordingly, utilizing a syngeneic, tumor-cell xenograft cSCC mouse model, we evaluated the effect of CXCL17 deletion on cSCC tumor-immune evasion and elucidated the underlying mechanism. Deletion of CXCL17 was associated with a significant reduction in tumor volume compared to the wild-type counterparts. Further, CXCL17 deleted cSCC tumor cell xenografts exhibited a significant increase in CD8+, cytotoxic T cells in the tumor microenvironment, suggesting an important role of CXCL17 in mediating tumor-immune evasion. Interestingly, treatment with CXCL17 induced macrophage M2 polarization and promoted macrophage efferocytosis via modulating efferocytotic machinery proteins such as MERTK, TIM4, GAS6 and AXL. Our studies have established substantial evidence for the role of CXCL17 in modulating tumor-cell extrinsic properties to affect the progression of cSCC.

Citation Format: Alok R. Khandelwal, Rema Anisha Kandula, Emily Daniel, Md Maksudul Alam, Henry Craighead, Tara Moore-Medlin, Cherie-Ann O. Nathan. Chemokine (C-X-C motif) ligand 17 promotes cutaneous squamous cell carcinoma via modulating tumor-immune evasion. [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 4448.
Abstract 4455: Protein phosphatase 4 inhibition stimulates anti-tumor immunity in ovarian cancer
Authors: Raja Remya , Wu Christopher , Bassoy Esen Y. , Rubino Thomas , Utagawa Emma , Magtibay Paul , Butler Kristina , Curtis Marion
Published: April 2023

Background: Increased infiltration of T cells into ovarian tumors has been repeatedly shown to be predictive of enhanced patient survival. However, despite the evidence of an active immune response in OC, immune checkpoint blockade therapy has been ineffective. Recently studies have shown that deficiencies in the DNA damage response (DDR) can drive increased genomic instability and tumor immunogenicity. One target involved in the DDR that has the potential to be of therapeutic value is protein phosphatase 4 (PP4); however, the effect of PP4 deficiency on anti-tumor immunity remain unknown.

Results: Our results show that PP4 inhibition combined with carboplatin leads to increased carboplatin sensitivity, DNA damage, and micronuclei formation. Using a panel of ovarian cancer cells, we show that PP4 inhibition triggers inflammatory signaling via NF-κB and STAT1 activation resulting in increased expression of pro-inflammatory cytokines including IFNβ1, CCL5, CXCL10, and IL-6. Moreover, conditioned media from OC cells treated with the combination of PP4 inhibitor and carboplatin significantly increased migration of both CD8 T cell and NK cells over carboplatin treatment alone. Knockdown of STING in OC cells significantly abrogated the increase in CD8 T cell migration induced by PP4 inhibition. PPP4C or PPP4R3B knockdown resulted in strong induction of NK cell IFN-γ, increased degranulation, and increased NK cell-mediated cytotoxicity against OC cells. Stable knockdown of PP4C in a syngeneic, immunocompetent mouse model of ovarian cancer resulted in significant reduction of tumor growth in vivo. PP4C low tumors had increased infiltration of CD161+ NK cells and CD4+ T cells. Addition of low dose carboplatin treatment in vivo led to increased CD8+ T cell infiltration in PP4C low tumors when compared to the untreated groups.

Conclusions: Our work has identified a role for PP4 inhibition in promoting anti-tumor immune activation. These findings provide the rationale for combining PP4 inhibitors with immunotherapy as a new approach in ovarian cancer treatment.

Citation Format: Remya Raja, Christopher Wu, Esen Y. Bassoy, Thomas Rubino, Emma Utagawa, Paul Magtibay, Kristina Butler, Marion Curtis. Protein phosphatase 4 inhibition stimulates anti-tumor immunity in 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 4455.
Abstract 4468: Tumor-derived extracellular vesicles transmit retroelement and pericentromeric RNAs to drive proinflammatory and DNA damage responses in stromal fibroblasts and immune cells
Authors: Evdokimova Valentina , Ruzanov Peter , Gassmann Hendrik , Stein Lincoln D. , Sorensen Poul H. , Burdach Stefan , Radvanyi Laszlo
Published: April 2023

Chronic cancer-associated inflammation and immunosuppression are common features in most patients with solid malignancies. The causes of this chronic inflammatory-immunosuppressive state are still largely undefined. We hypothesized that selective RNAs can be secreted by cancer cells in extracellular vesicles (EVs) and may trigger proinflammatory responses in target cells, leading to chronic inflammation linked to immune cell dysfunction and immunosuppression. We found that tumor cell lines from pancreatic ductal adenocarcinoma (PDAC), prostate cancer (PCa) and from pediatric cancer such as Ewing sarcoma (EwS) continuously secrete large numbers of small (40-200 nm) EVs. In contrast to non-transformed fibroblasts, cancer cell-derived EVs are enriched with large subsets of retroelement and pericentromeric transcripts, including LINE, SINE and HERV retroelements, and human satellite 2 and 3 (HSAT2,3) RNAs. These virus-like RNAs were highly elevated in plasma EVs from EwS patients but not in healthy donors. Some of them, including HERV-K and HSAT2, were detected in peripheral blood myeloid cells with CD33+HLA-DR− immunosuppressive phenotypes, and these cell populations were expanded in EwS patients compared to healthy donors. Using mouse xenografts and in vitro models, we also found that at least some of these RNAs, such as HSAT2, are transmitted to stromal fibroblasts and immune cells in the tumor microenvironment. They also accumulated in fibroblasts after treatment with EwS EVs, coincident with the induction of proinflammatory and DNA damage responses. Prolonged exposure of fibroblasts to EwS EVs also led to mitotic defects and senescence. Expression and dissemination of these highly immunogenic virus-like RNAs in EVs may thus be a common feature of multiple human malignancies, potentially affecting host cells in the local and systemic tumor environment. This, in turn, may induce chronic inflammation contributing to an overall immunosuppressed state in patients.

Citation Format: Valentina Evdokimova, Peter Ruzanov, Hendrik Gassmann, Lincoln D. Stein, Poul H. Sorensen, Stefan Burdach, Laszlo Radvanyi. Tumor-derived extracellular vesicles transmit retroelement and pericentromeric RNAs to drive proinflammatory and DNA damage responses in stromal fibroblasts and immune 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 4468.
Abstract 4471: Reprogramming “cold” NF1 malignancies into “hot” tumors for immunotherapy
Authors: Madana Laasya , Le Lu Q. , Somatilaka Nipunika , McKay Renee
Published: April 2023

Introduction: Neurofibromatosis Type 1 (NF1) results from mutations in the NF1 gene that inactivate the tumor suppressor, neurofibromin. This leads to hyperactive RAS signaling that predisposes NF1 patients to tumor development. Over time, some of these tumors can develop into malignant peripheral nerve sheath tumors (MPNST) which are currently incurable.Immune checkpoint blocking (ICB) programs a patient’s immune system to enhance tumor destruction. However, MPNSTs are cold tumors characterized by low immune cell presence in the tumor microenvironment. Interestingly, MPNSTs show checkpoint protein PD-L1 expression suggesting ICB as potential therapy for MPNST, given the ability to increase immune cell density in the tumor microenvironment. Activation of the intracellular receptor stimulator of interferon genes (STING) enhances antitumor immunity through the induction of pro-inflammatory cytokines and chemokines, including type I interferons. Cyclic GMP-AMP synthase (cGAS) is an enzyme that once bound to cytosolic DNA, synthesizes cyclic GMP-AMP (cGAMP), which activates STING to induce inflammatory cytokines and other immune mediators. Preclinical studies using mouse tumor models have assessed the efficacy of STING agonists that trigger the cGAS-STING-IFN axis, ultimately leading to augmented innate immunity and a T cell-rich tumor environment. Additionally, combining STING agonists with ICB has a synergistic effect in treating tumors. Therefore, we hypothesize that treatment with STING agonists would turn “cold” MPNSTs into “hot” tumors making them susceptible to targeting with ICB.

Methods: We treated MPNST cell lines with synthetic STING agonist ADU-S100 for varying durations of 8, 18, 24, and 48 hours. At the end of the treatment, cells were harvested for qRT-PCR and immunoblot analysis.

Results: We measured STING-IFN pathway activation through immunoblotting and observed that phosphorylation of STING effector proteins - a readout of STING activation – was increased followingby 8 hours after treatment. qRT-PCR analysis showed that STING target cytokine/chemokine gene expression was also upregulated by 8 hours after ADU-S100 treatment.

Conclusions: Theise data demonstrates that ADU-S100 was able to activate the STING pathway in MPNST cell lines leading to proinflammatory cytokine/chemokine production. We will next test STING agonist in vivo use to determine whether ADU-S100 treatment inin mouse MPNST modelss of MPNST to is able to reprogram the tumor microenvironment into an immune inflamed one amenable to immunotherapy.

Citation Format: Laasya Madana, Lu Q. Le, Nipunika Somatilaka, Renee McKay. Reprogramming “cold” NF1 malignancies into “hot” tumors for immunotherapy. [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 4471.
Abstract 4587: Vascular-derived signature imprinted by tumor microenvironment-dependent transcriptional memory predicts colon cancer prognosis
Authors: Naschberger Elisabeth , Fuchs Maximilian , Dickel Nicholas , Kunz Meik , Anchang Charles G. , Demmler Richard , Popp Bernt , Ekici Arif B. , Uebe Steffen , Geppert Carol I. , Günther Claudia , Merkel Susanne , Schellerer Vera S. , Stürzl Michael
Published: April 2023

Background: Antiangiogenic therapy is part of the guideline therapy of colorectal cancer (CRC). Surprisingly, the impact of the tumor microenvironment (TME) on tumor vessel endothelial cells (TECs) is largely unclear. The aim of this study was to investigate the presence of a TME-dependent transcriptional memory in TECs isolated from patients and to exploit it to retrieve signatures that characterize TECs in different intratumoral TMEs with impact on patient outcome.

Methods: ECs from tumor and normal colon tissues, PBMCs and tumor cells were isolated from CRC patients with different prognostic TMEs. Cells were analyzed by qPCR, immunocytochemistry and multi-omics (transcriptomics, EPICmethylation chips, exome sequencing). Integrative bioinformatics was used to identify TME-dependent memory genes predicting prognosis and scRNASeq to validate endothelial gene expression in CRC tissues.

Results: Ultrapure TECs were isolated from CRC with different prognostic TMEs (Th1 vs. non-Th1) and systematically compared by multi-omics. A transcriptional memory differentiating the respective TEC groups was identified. This in vivo imprinted transcriptional memory was preferentially regulated by epigenetic DNA methylation but not by genomic alterations and was different from an in vitro primed transcriptional memory to IFN-γ. Moreover, it was specific for TECs and not observed in CAFs. With integrative bioinformatics a TME-dependent memory signature was extracted and its expression in TECs in CRC tissues was confirmed by scRNASeq. Notably, the identified signature predicted the prognosis of CRC patients.

Conclusion: We identified a tumor vessel-derived TME-dependent transcriptional memory signature that was manifested by epigenetic mechanisms and allowed tumor vessel-based prediction of CRC patients prognosis.

Citation Format: Elisabeth Naschberger, Maximilian Fuchs, Nicholas Dickel, Meik Kunz, Charles G. Anchang, Richard Demmler, Bernt Popp, Arif B. Ekici, Steffen Uebe, Carol I. Geppert, Claudia Günther, Susanne Merkel, Vera S. Schellerer, Michael Stürzl. Vascular-derived signature imprinted by tumor microenvironment-dependent transcriptional memory predicts colon cancer prognosis. [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 4587.
Abstract 4601: Vitamin D supplementation attenuates resistance to anti-angiogenic therapy in colorectal cancer liver metastases
Authors: Rada Miran , Krzywon Lucyna , Kapelanski-Lamoureux Audrey , Petrillo Stephanie , Lazaris Anthoula , Metrakos Peter
Published: April 2023

Colorectal cancer liver metastasis (CRCLM) is one of the deadliest cancers. CRCLM tumours have two distinct histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours are angiogenic, while their RHGP counterparts are vessel co-opting. The patients with RHGP tumours showed poor response to anti-angiogenic agents, as well as a worse prognosis. Herein, we conducted a retrospective cohort study that comprised 106 CRCLM patients to examine the effect of vitamin D supplementation on the HGPs of the tumours and the 5-year overall survival (OS). Interestingly, we found an inverse correlation between vitamin D supplementation and the presence of RHGP tumours in CRCLM patients. Additionally, the population who used vitamin D supplementation had significantly better 5-year OS. Moreover, our in vivo results suggested that vitamin D supplementation significantly improves the response of CRCLM tumours to anti-angiogenic therapy. Mechanistically, we found that vitamin D can suppress cancer cell motility, which is essential for the development of vessel co-option tumours and resistance to anti-angiogenic therapy. Collectively, this study suggests vitamin D supplementation is a promising way to attenuate resistance to anti-angiogenic therapy and improve the prognosis of CRCLM patients.

Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Anthoula Lazaris, Peter Metrakos. Vitamin D supplementation attenuates resistance to anti-angiogenic therapy in colorectal cancer liver metastases. [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 4601.