bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 1673: Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and solid tumors
Authors: Joo Min Sung , Lee JaeYung , Kim Eun-Jung , Ki Dong Hyuk , Choi Hunmi , Nam Joonwoo , Park Jaewoo , Kang Keon Wook , Han Wooseok
Published: April 2023

Molecular glue degraders (MGDs) of neo-substrates that function by hijacking the CRBN E3 ligase are clinically validated as therapeutics for the treatment of hematological malignancies. Novel MGDs of GSPT1, a translation termination factor, elicit dysregulated protein translation termination and subsequent induction of TP53-independent apoptosis in acute myeloid leukemia (AML) cells through activation of the integrated stress response. In addition, dysregulation of translation termination triggered by GSPT1 degradation appears to be cytotoxic specifically to MYC-driven cancers including solid tumors with translational addiction. Phase 1 clinical trials of three novel GSPT1 MGDs have been recently launched for the treatment of AML and/or MYC-driven solid tumors (NCT02848001, NCT04336982, NCT05546268, and NCT05144334). Herein, we present novel GSPT1 MGDs and their pre-clinical results against AML and solid tumors. Our current lead GSPT1 MGDs induced rapid, potent, and durable degradation of GSPT1, resulting in strong inhibition of tumor cell growth in a variety of cell lines of MYC-driven solid tumor and blood cancer (AML and acute lymphoblastic leukemia). Moreover, in ex-vivo assays using a panel of patient-derived primary AML cells, C-10386 was highly sensitive with EC50s at the nanomolar range. Furthermore, a related analogue (C-14207) showed excellent rodent PK profiles and demonstrated dose-dependent PKPD relationship and excellent efficacy in the NCI-H1155 NSCLC xenograft model. Finally, our current lead compounds showed safer profiles in various normal cells compared to other known GSPT1 degraders. Collectively, we have identified novel GSPT1 MGDs as promising development candidates for the treatment of AML and solid tumors.

Citation Format: Min Sung Joo, JaeYung Lee, Eun-Jung Kim, Dong Hyuk Ki, Hunmi Choi, Joonwoo Nam, Jaewoo Park, Keon Wook Kang, Wooseok Han. Discovery of potent, selective, and orally bioavailable GSPT1 degraders and their pre-clinical anti-tumor activity in acute myeloid leukemia and 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 1673.
Abstract 1741: Inhibition of pcsk9 impairs the development of vessel co-option and potentiates anti-angiogenic therapy in colorectal cancer liver metastases
Authors: Rada Miran , Krzywon Lucyna , Kapelanski-Lamoureux Audrey , Petrillo Stephanie , Reynolds Andrew , Lazaris Anthoula , Seidah Nabil , Metrakos Peter
Published: April 2023

Colorectal cancer liver metastatic (CRCLM) tumours present as two main histopathological growth patterns (HGPs) including desmoplastic HGP (DHGP) and replacement HGP (RHGP). The DHGP tumours obtain their blood supply by sprouting angiogenesis, whereas the RHGP tumours utilize an alternative vascularisation known as vessel co-option. In vessel co-option, the cancer cells hijack the mature sinusoidal vessels to obtain blood supply. Vessel co-option has been reported as an acquired mechanism of resistance to anti-angiogenic treatment in CRCLM. Herein, we show the connection between serum cholesterol concentration and vessel co-option development in CRCLM. Our clinical data suggested that the elevation of serum cholesterol levels correlates with the risk of developing vessel co-opting tumours. Moreover, inhibition of PCSK9, the key modulator of cholesterol metabolism, significantly attenuated the development of vessel co-opting CRCLM tumours and sensitized the tumours to anti-angiogenic therapy in vivo. Altogether, these data suggest the importance of cholesterol in the development of vessel co-option tumours and propose that inhibiting PCSK9 is a promising strategy to overcome resistance to anti-angiogenic therapy in CRCLM.

Citation Format: Miran Rada, Lucyna Krzywon, Audrey Kapelanski-Lamoureux, Stephanie Petrillo, Andrew Reynolds, Anthoula Lazaris, Nabil Seidah, Peter Metrakos. Inhibition of pcsk9 impairs the development of vessel co-option and potentiates 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 1741.
Abstract 1877: Tripokin: potential best-in-class for tumor targeted interleukin-2 (IL2) potentiated by tumor necrosis factor (TNF)
Authors: Prodi Eleonora , Corbellari Riccardo , Matasci Mattia , Neri Dario , De Luca Roberto
Published: April 2023

Among the different pharmacological approaches for cancer treatment, antibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, capable of boosting the immune system to attack tumor cells as a result of a selective accumulation of pro-inflammatory molecules at the site of disease. When used as single agents, immunocytokines are often not able to cure mice and patients. However, it has been shown by our group that the combination of IL2- and TNF- based products was able to completely eradicate tumors in mouse models and to induce complete responses in cancer patients. We have previously described a novel class of immunocytokine products, termed “potency-matched dual cytokine antibody fusion proteins”, consisting of a tumor-targeting antibody (the F8 antibody, specific to the alternatively spliced EDA domain of fibronectin), simultaneously fused to both IL2 and TNF. To match biological activity of the two payloads a single-point mutation was inserted in the TNF sequence and the resulting product, named IL2-F8-TNFmut was able to selectively localize to tumors with excellent tumor-to-organ ratios and it was found to completely eradicate soft-tissue sarcomas in immunocompetent mice, which did not respond to standard chemotherapy. Moreover, the immunocytokine was able to induce complete responses in a variety of mouse models of cancer. The therapeutic activity was further improved when IL2-F8-TNFmut was used in combination with immune checkpoint inhibitors. At the mechanistic level we observed that the anticancer activity was completely abrogated when CD4+ and CD8+ T cells were depleted, while the contribution of NK cells was negligible. We now report the generation of a new potency-matched dual cytokine antibody fusion protein, named Tripokin based on the L19 antibody, specific to the alternatively spliced EDB domain of fibronectin. Compared to the previous product, Tripokin showed a favorable pharmacokinetic profile in monkey, an excellent localization to neoplastic lesions in mice and was easier to formulate for further clinical applications. When tested in tumor bearing mice, Tripokin revealed a superior anti-cancer activity compared to other IL2-based products.The results obtained in this work provided a rationale for future clinical translation activities using Tripokin as potential best-in-class tumor targeted IL2 product.

Citation Format: Eleonora Prodi, Riccardo Corbellari, Mattia Matasci, Dario Neri, Roberto De Luca. Tripokin: potential best-in-class for tumor targeted interleukin-2 (IL2) potentiated by tumor necrosis factor (TNF) [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 1877.
Abstract 2272: Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast cancer
Authors: Eisa Nada , Crowley Vincent M. , Elahi Asif , Kommalapati Vamsi K. , Korkaya Hasan , Debbab Abdessamad , Blagg Brian , Chadli Ahmed
Published: April 2023

Low response rates and immune-related adverse events limit the impact of cancer immunotherapy. To improve clinical outcomes, preclinical studies have shown that combining immunotherapies with N-terminal Hsp90 inhibitors resulted in improved efficacy, even though induction of an extensive heat shock response (HSR) with these inhibitors limited their clinical efficacy as monotherapies. We discovered that Enniatin A (EnnA) binds to the interface between the middle domains of the Hsp90 dimer and destabilizes Hsp90 client oncoproteins without inducing an HSR. EnnA induces cancer cell immunogenic cell death in aggressive breast cancer models and exhibits superior anti-tumor activity compared to Hsp90 N-terminal inhibitors. EnnA reprograms the tumor microenvironment in syngeneic mouse models to promote CD8+ T cell-dependent anti-tumor activity mediated through a reduced level of PD-L1 and activation of CX3CR1 pathway. We propose that EnnA is a promising anti-tumor agent with a mechanism of action involving immunogenic cancer cell toxicity and mobilization of CD8+ T cells into the tumor site.

Citation Format: Nada Eisa, Vincent M. Crowley, Asif Elahi, Vamsi K. Kommalapati, Hasan Korkaya, Abdessamad Debbab, Brian Blagg, Ahmed Chadli. Targeting the chaperone Hsp90 to activate the immune system and eradicate the triple negative breast 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 2272.
Abstract 2637: Novel folate receptor alpha-directed antibody-drug conjugate PRO1184 demonstrates broad antitumor activity with a promising safety profile in preclinical models
Authors: Wang Lei , Liu Haidong , Zhou Chang , Han Tae , Zhao Baiteng , Chen Zhu
Published: April 2023

Folate receptor α (FRα) is overexpressed in a range of solid tumors with limited expression in normal tissues, hence an attractive target for an antibody-drug conjugate (ADC). PRO1184 is comprised of a human monoclonal antibody that selectively binds FRα, a novel cleavable hydrophilic linker, and a topoisomerase 1 inhibitor payload, exatecan. Previous studies established that a) PRO1184 exerts potent antitumor activity in cell-derived xenograft (CDX) models representing ovarian, non-small cell lung, and breast cancer, b) with pharmacokinetics (PK) akin to that of the unconjugated parent antibody in rats, and c) with a preliminary safety profile that was more favorable than a DXd-based ADC in cynomolgus monkeys. Further characterization of the activity and safety of PRO1184 is reported here. PRO1184 displays strong binding affinity, rapid internalization, and potent cytotoxicity with the HCC1954 (breast cancer), JEG-3 (choriocarcinoma), and HEC-1-A (endometrial cancer) cells, in vitro. PRO1184 at a single dose of 5 mg/kg produced marked tumor growth inhibition in CDX models with all three cell lines. In 14 patient-derived xenograft (PDX) models encompassing ovarian, gastric, breast, and non-small cell lung cancer, PRO1184 at a single dose of 5 mg/kg elicited robust antitumor activity in all four tumor types, with ORR and CR accomplished in 10 and 3 out of the 14 models, respectively. Antitumor activity was observed in xenografts with both high and low FRα expression, suggesting that PRO1184 may benefit patients with a wide range of FRα expression. Two DM4-based benchmarking ADCs produced modest to negligible tumor growth inhibition in head-to-head comparisons in the CDX and PDX studies. In a GLP cynomolgus monkey toxicity study for PRO1184, main treatment-related findings were consistent with those associated with exatecan and included reversible gastrointestinal and hematologic toxicities. There were no toxicity findings in lungs, which may translate to a lower risk of interstitial lung disease (ILD) compared to DXd-based ADCs in the clinic. In summary, PRO1184 is a promising development candidate for the treatment of FRα-expressing solid tumors. A first in human phase 1/2 study in patients with advanced solid tumors is currently recruiting (NCT 05579366).

Citation Format: Lei Wang, Haidong Liu, Chang Zhou, Tae Han, Baiteng Zhao, Zhu Chen. Novel folate receptor alpha-directed antibody-drug conjugate PRO1184 demonstrates broad antitumor activity with a promising safety profile in preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2637.
Abstract 2642: BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation
Authors: Wan Weili , Zhao Shuwen , Zhuo Shi , Zhang Yong , Chen Lan , Li Gangrui , Renshaw Blair , Khalili Jahan Salar , Xiao Sa , Zhu Yi
Published: April 2023

EGFR and HER3, members of the human epidermal growth factor receptor (ErbB) family, are targeted in cancer therapy due to their over-expression and pathway dependence in common human epithelial carcinoma tumors. To develop a promising therapeutic anti-tumor agent, we generated BL-B01D1, an EGFR×HER3-targeting ADC, which can bind to EGFR and/or HER3 positive cells and is expected to be superior to anti-EGFR and anti-HER3 ADCs. It is comprised of a bispecific antibody against EGFR/HER3 (SI-B001), a cathepsin B cleavable linker, and a novel topoisomerase I inhibitor agent (Ed-04), which is a derivative of the alkaloid camptothecin, driving cell cycle arrest at the S phase and subsequent apoptosis. BL-B01D1 achieves a high drug-to-antibody-ratio (DAR=8) with a highly stable linker.

The pharmacological potential of this ADC was evaluated in comparison to its parental single antigen-targeting ADCs in xenograft models composed of either the human colorectal cancer cell line SW620 or pancreatic cancer cell line BxPC3. The tumor inhibition activity of BL-B01D1 was compared with ADCs prepared from each parental anti-EGFR or anti-HER3 mAb conjugated with the same linker and payload. The bispecific ADC, BL-B01D1 exhibited stronger tumor inhibition capacity than the anti-EGFR ADC and the anti-HER3 ADC separately.

The preclinical studies suggest BL-B01D1, as an EGFR×HER3-targeting ADC, might be a promising novel agent with activity toward a broad range of human cancers. The clinical phase I has been progressing and the available data exhibit excellent efficacy but low levels of targeted toxicity in the non-small cell lung cancer (NSCLC) treatment setting. Overall, these data suggest BL-B01D1 has potential to serve as a novel, efficacious therapeutic agent for NSCLC with similar therapeutic impact as DS-8201 has in breast cancer treatment.

Citation Format: Weili Wan, Shuwen Zhao, Shi Zhuo, Yong Zhang, Lan Chen, Gangrui Li, Blair Renshaw, Jahan Salar Khalili, Sa Xiao, Yi Zhu. BL-B01D1, a novel EGFR×HER3-targeting ADC, demonstrates robust anti-tumor efficacy in preclinical evaluation [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 2642.
Abstract 2693: Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models
Authors: Knoerzer Deborah , Reddy Anupama , Box Jessica A. , Groover Anna , Kreider Brent , Teresk Martin , Emery Caroline M.
Published: April 2023

The BRAFV600E mutation occurs in approximately 7% of colorectal cancer (CRC). BRAF plus EGFR inhibition (encorafenib with cetuximab) is an FDA approved treatment option for adult patients with metastatic CRC. Ultimately, patients develop resistance leading to disease progression. The addition of a MEK inhibitor, binimetinib, did not confer overall survival benefit. We hypothesized that addition of ERK inhibition would increase magnitude and duration of response to BRAF plus EGFR inhibition by overcoming MAPK-related acquired resistance mechanisms. ERK is the terminal master regulator kinase of the RAS-MAPK pathway, therefore, targeting this node is likely to be effective in the context of numerous mechanisms of acquired resistance that reactivate the MAPK pathway.

Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. The efficacy of ulixertinib, in combination with EGFR inhibition (cetuximab), plus BRAF inhibition (encorafenib), was assessed in CRC cell line derived xenograft models harboring BRAFV600E mutations. The triple combination resulted in superior tumor growth inhibition compared to dosing of any single agent or doublet. RNA sequencing was performed on treated tumor samples. Expression of the mutant BRAF allele was readily confirmed from RNA sequencing data. Gene expression analysis showed differential expression of MAPK pathway genes in triple combination treated groups versus single or doublet therapy.

A complete response to ulixertinib in combination with cetuximab and encorafenib for the treatment of a patient with metastatic CRC has been reported (Stuhlmiller, Timothy Joseph, et al. "Updated clinical outcomes from ULI-EAP-100, an intermediate expanded access program for ulixertinib (BVD-523)." (2022): e15101-e15101). The patient was treated under the Expanded Access Protocol (NCT04566393) for compassionate use access to ulixertinib. Preclinical data and clinical complete response warrants further investigation of ulixertinib plus BRAF and EGFR inhibition.

Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. Combining ulixertinib (ERK1/2 Inhibitor) with EGFR and BRAF inhibition yields significant efficacy in preclinical BRAFV600E mutant colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2693.
Abstract 2889: Novel subset of granulocytic MDSCs as immunosuppressive regulators and therapeutic targets in gastric cancer
Authors: Iwasawa Takumi , Yamauchi Suguru , Fukunaga Tetsu , Orita Hajime , Kato Kazunori
Published: April 2023

The development and progression of cancers are frequently promoted by immunosuppressive cells, such as Treg and myeloid-derived suppressor cells (MDSCs) mediated by various immune checkpoint molecules. Recently, the immune checkpoint inhibitor anti-PD-1 neutralizing antibody has become available for the first-line treatment of gastric cancer (GC) in Japan. However, there is no correlation between PD-1 or PD-L1 expression in Treg or GC tissues and clinical responses to anti-PD-1 antibody. MDSCs are immature myeloid cells thought to suppress immune cell action, but the functional cell surface markers that define MDSCs correlated with cancer progression has not yet been clarified well. In this study, we identified a new subset of potential therapeutic and diagnostic targets for MDSCs in GC patients. Significantly higher levels of immune checkpoint molecules, PD-1 and PD-L1, were expressed on granulocytic MDSCs from advanced than early-stage of GC patients. Interestingly, we found that a subset of G-MDSCs expressed not only PD-1 but also PD-L1 and the pretreatment of G-MDSCs with anti-PD-1 antibody ameliorated T cell responses in vitro. We also found that G-MDSCs isolated from patients treated with anti-PD-1 antibody had a lower ability to suppress T cells. These data indicate that a novel subset of G-MDSCs expressing PD-1 found in advanced GC could be novel therapeutic targets.

Citation Format: Takumi Iwasawa, Suguru Yamauchi, Tetsu Fukunaga, Hajime Orita, Kazunori Kato. Novel subset of granulocytic MDSCs as immunosuppressive regulators and therapeutic targets in gastric 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 2889.
Abstract 2977: A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy
Authors: Shang Chengzhang , An Gao , Guo Yuming , Zhang Ellen , Lin Qingcong , Yang Yi
Published: April 2023

Antibody-drug conjugates (ADC) are a therapeutic modality that combines the advantages of potent killing from small molecule cytotoxic payload and highly specific targeting from monoclonal antibodies. By targeting dual tumor-associated antigens (TAA), the bispecific ADC (BsADC) serves as a promising therapeutic strategy that can further increase tissue specificity and selectivity. HER2 and TROP2 are two TAAs that are commonly expressed and co-expressed by multiple tumor types, including gastric, colorectal, bladder, breast, and non-small-cell lung cancer (NSCLC). Of note, TROP2 expression has been detected in a wide range of HER2-low expressing tumors. These data led us to predict that targeting HER2 and TROP2 with a BsADC would provide therapeutic benefit, especially for patients with HER2-low cancers. Hence, we generated YH012, a first-in-class BsADC that contains a fully human bispecific anti-HER2/TROP2 antibody conjugated with monomethyl auristatin E (MMAE) via a protease-cleavable linker. In vitro, YH012 demonstrated enhanced affinity, internalization, and tumor selectivity compared to its parental monoclonal and monovalent anti-HER2 or anti-TROP2 antibodies. In vivo, YH012 showed strong anti-tumor activity in multiple cell line-derived and patient-derived xenografts (CDX and PDX) of NSCLC, gastric, pancreatic, and breast cancer. Moreover, YH012 exhibited superior anti-tumor efficacy than benchmark antibodies in both HER2-positive and HER2-low xenograft models, indicating that YH012 has a potent and broad therapeutic effect. In summary, YH012 has the advantages of increased potency, tissue specificity, and reduced toxicity as a novel BsADC that can be further exploited to treat HER2 and TROP2 co-expressing tumors, especially HER2-low tumors.

Citation Format: Chengzhang Shang, Gao An, Yuming Guo, Ellen Zhang, Qingcong Lin, Yi Yang. A first-in-class anti-HER2/TROP2 bispecific antibody-drug conjugate (YH012) exhibits potent anti-tumor efficacy [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 2977.
Abstract 4298: Machine learning-based model for survival prediction after immunotherapy in patients with solid tumor
Authors: Fala Salma Y. , Osman Mohamed
Published: April 2023

Background: Immune checkpoint inhibitors (ICIs) have led to a paradigm shift in solid tumors treatment. However, not all patients respond favorably to these drugs, highlighting the need for reliable predictions to achieve more personalized care and better management. This study aimed to create and validated ML model to predict survival in solid tumors patients receiving ICIs.

Methods: We obtained clinical and genomic data from cBio Cancer Genomics Portal. Data were randomly divided into a training set (80%) and a validation set (20%). light gradient boosting algorithm was trained to predict patients’ survival at different time points.

Results: We identified 1660 patients with a median survival of 18 months. LGB yielded AUCs of 67.91% at 1 year, 79.89.6% at 2 years, and 79.75% at 3 years, respectively. The most important predictors that influenced the performance of the model in predicting 3-year-survival were: Age (22.89%), tumor mutational burden (18.24%), and tumor purity (13.23%). Moreover, multivariate analysis was performed and drug type was identified as an independent prognostic indicator (P< .001). So, a Subgroup analysis was done and the OS rates were: 98.57%, 75.55%, 33.84% in patients who received CTLA-4, 98.57%, 75.55%, 33.84% with PD-1/PD-L1, and 97.99%, 9.94%, 4.62% with combo treatment, at 1-, 3-, and 5 years, respectively.

Conclusion: Our ML-based model that integrates both clinical and genomic data is an improved tool for survival prediction, enabling an accurate risk classification and leading to a more precise decision-making. Moreover, this study highlights the importance of age and tumor microenvironment as the main contributors in making survival prediction in patients receiving ICIs. Table. Performance in survival prediction among training and testing sets

Table 1. Survival Average AUC Average Accuracy Survival Duration Positive Predictive Value (Precision) Sensitivity (Recall) 1-year 67.91% 63.18% <12 months 58% 54% >=12 months 67% 70% 2-years 79.89% 78.70% <24 months 86% 84% >=24 months 62% 65% 3-years 79.75% 86.02% <36 months 95% 89% >=36 months 45% 65%

Citation Format: Salma Y. Fala, Mohamed Osman. Machine learning-based model for survival prediction after immunotherapy in patients with solid tumor. [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 4298.
Abstract 432: Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader
Authors: Teh Jessica , Bessonett Shannon , Wu Wendy , Kuhlberg Christopher , Wynne Alissa , Landrette Sean , Andreoli Monica , Bortolon Elizabeth , Pizzano Jennifer , Gedrich Richard , Taylor Ian
Published: April 2023

ARV-471 is an orally bioavailable cereblon (CRBN)-based PROteolysis-TArgeting Chimera (PROTAC®) small molecule that demonstrates superior ER degradation and anti-tumor activity compared to fulvestrant in endocrine sensitive and resistant xenograft models and has shown significant ER degradation and promising clinical benefit in late-line ER-positive breast cancer patients. Innate and acquired drug resistance limits the response to and durability of many cancer therapies. To identify potential mechanisms of resistance to ARV-471, we generated ARV-471-resistant MCF7 cell lines which were then characterized using DNA, RNA and functional proteomic profiling. Acquired resistance to ARV-471 was associated with downregulation of ER protein expression and signaling and upregulation of HER family (EGFR, HER2, HER3) and MAPK/AKT signaling. NRAS copy number gain was also observed, which was accompanied by increased NRAS expression. Although EGFR, HER2 and HER3 expression and activation were upregulated, no corresponding genomic alterations were observed in resistant cells. Importantly, we show that NRAS and EGFR overexpression in MCF7 cells conferred resistance to ARV-471 in vitro. Furthermore, ARV-471-resistant cells with HER pathway upregulation were sensitive to EGFR and pan-HER inhibitors. Unlike recent reports indicating the association of E3 ligase alterations with PROTAC resistance, CRBN mutations/loss were not detected, nor were ESR1 mutations. CRBN knockout in ER+ breast cancer cells did not confer resistance to ARV-471, consistent with ARV-471 possessing ER antagonist activity independent of its degrader activity. Together, these data suggest that acquired resistance to ARV-471 may be associated with alterations within Receptor Tyrosine Kinase/MAPK signaling pathways rather than ER signaling or E3 ligase machinery.

Citation Format: Jessica Teh, Shannon Bessonett, Wendy Wu, Christopher Kuhlberg, Alissa Wynne, Sean Landrette, Monica Andreoli, Elizabeth Bortolon, Jennifer Pizzano, Richard Gedrich, Ian Taylor. Mechanisms of acquired resistance to ARV-471, a novel PROTAC® estrogen receptor degrader [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 432.
Abstract 4500: Enedione derivates as a potential cancer treatment through the inhibition of COPZ1
Authors: Martins Allana C. , Barbosa Barbara Mitsuyasu , da Silveira Ingridhy O. Maia Freitas , Gomes Roberto
Published: April 2023

Cancer is a leading cause of death worldwide; it was responsible for approximately 10 million deaths in 2020. Besides surgery for tumor removal, the most common treatments available are chemotherapy and radiation, which are not selective, resulting in side effects such as pain, hair loss, nausea, and vomiting. They are also ineffective against stem-like and dormant tumor cells, which could lead to a relapse and/or metastasis. Consequently, the development of drugs with tumor-specific targets is needed. COPI is a coatomer responsible for the retrograde transport from Golgi complex (GC) to the endoplasmic reticulum (ER). In this context, we developed four compounds targeting disruption of GC through inhibition of COPI and previous results showed that compounds 1-4 significantly decrease cell viability of pancreatic cancer cell lines MIA PaCa-2 and AsPC-1, compared to hTERT-HPNE normal pancreatic cell line. In the present work, RT q-PCR confirmed that the two isoforms of the COPI ζ subunit COPZ1 and COPZ2 are expressed at similar levels in normal cells while COPZ2 is downregulated in tumor cell lines. Our in vitro results demonstrated that compounds 1-4 decreased cell viability of breast cancer (HCC1143) and melanoma (A-395) cell lines. The tested compounds are able to target COPZ1-dependent tumor cells, therefore they are great candidates for further studies aiming to develop a selective treatment for cancer.

Citation Format: Allana C. Martins, Barbara Mitsuyasu Barbosa, Ingridhy O. Maia Freitas da Silveira, Roberto Gomes. Enedione derivates as a potential cancer treatment through the inhibition of COPZ1. [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 4500.
Abstract 4991: Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC)
Authors: Tanim K.M. , DeRyckere Deborah , Graham Douglas K.
Published: April 2023

MERTK is a transmembrane receptor that belongs to the TAM (TYRO3, AXL, MERTK) family of receptor tyrosine kinases. The role of MERTK in cancer progression and resistance to therapies are reported in many cancer types, including non-small cell lung cancer (NSCLC). In canonical signaling, MERTK is localized at the cell membrane and mediates intracellular signal transduction pathways. Non-canonical signaling of receptor tyrosine kinases (RTKs) has been reported, including signaling which occurs when RTKs translocate to the nucleus. Our group previously reported nuclear localization of MERTK in leukemia cells and we now extend these findings to non-small cell lung cancer. We found exogenous MERTK localized to the nucleus in cells transfected with a plasmid expressing wild-type MERTK. Additionally, endogenous nuclear MERTK was phosphorylated, suggesting that MERTK may have a functional role in the nucleus. MERTK kinase inhibitor MRX-2843 modulates its nuclear translocation. Introducing point mutations to MERTK autophosphorylation sites diminished nuclear translocation in comparison to cells transfected with wild-type MERTK. Our analysis of proteins that may interact with MERTK to regulate nuclear localization and function demonstrated co-immunoprecipitation of nuclear MERTK and STAT1. Current studies are underway to further explore nuclear MERTK functions and how these roles may be modulated upon interaction with STAT1.

Citation Format: K.M. Tanim, Deborah DeRyckere, Douglas K. Graham. Phosphorylation of MERTK is required for nuclear localization in non-small cell lung cancer (NSCLC). [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 4991.
Abstract 5496: Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality
Authors: Luna Pamela , Acharya Ganesh , Ochola Damieanus , Peddibhotla Swetha , Mani Chinnadurai , Reedy Mark B. , Palle Komaraiah
Published: April 2023

Ovarian cancer (OC) is a highly aggressive disease and the most lethal gynecologic malignancy in women. Although the majority of OC patients respond to chemotherapeutic drugs, more than 70% of the patients relapse and die as a result of chemoresistance. Therefore, novel therapeutics are warranted to prevent chemoresistance and treat the relapsed disease to improve prognosis. Many cancer cells depend on Glutamine as major carbon source and these cells have high Glutaminase (GLS) expression, an enzyme that converts Glutamine to Glutamate. Chemo-resistant OC cells have elevated levels of GLS, which confirms their increased dependency on glutamine metabolism. Based on these observations, we postulated that GLS inhibition may attenuate the aggressive growth of GLS high OC cells and may sensitize to the agents that can further potentiate these effects. Interestingly, GLS inhibition using a clinical-stage drug CB839 caused replication stress and activated DNA damage checkpoint protein 1 (CHK1) mediated cell cycle arrest. These novel findings suggested a role for CHK1 in protecting GLS inhibition-induced DNA damage by facilitating the timely repair of DNA breaks. Based on these observations, we hypothesized that GLS inhibition in combination with CHK1 inhibition may cause synergistic lethality in chemo-resistant and GLShigh OC cells. We evaluated the combination of GLS inhibitor CB839 and CHK1 inhibitor Prexasertib. Our results demonstrate that GLS inhibition-induced CHK1 phosphorylation is significantly attenuated by Prexasertib treatment. Similarly, combined treatment of CB839 and Prexasertib showed significantly elevated levels of DNA damage as measured by COMET assays, replication stress-mediated DNA damage responses, and synergistic OC cell lethality compared to individual drug treatments. Furthermore, CB839 and Prexasertib combination was more synergistic in cells that expressed high GLS compared to low GLS-expressing OC cells indicating the specificity of the combination of these drugs. Together, our studies identified a novel connection between metabolic and DNA damage checkpoint pathways in OC and propose a novel synergistic lethality-based combination therapy to treat chemo-resistant and aggressive OC.

Citation Format: Pamela Luna, Ganesh Acharya, Damieanus Ochola, Swetha Peddibhotla, Chinnadurai Mani, Mark B. Reedy, Komaraiah Palle. Glutaminase inhibition induces replication stress in ovarian cancer cells and inhibition of replication checkpoint causes synthetic lethality. [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 5496.
Abstract 6273: CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human tumors
Authors: Wang Long , Liu Yilin , Shi Hui , Liu Yuanyuan , Ouyang Qiugeng , Guo Jiannan , Wang Yiqin , Wang Youzhen , Xu Guoliang , Mi Yuan , Wu Haiping
Published: April 2023

MTAP deletion is common in about 15% of all human cancers and coincides with the deletion of tumor suppressor locus containing CDKN2A/B. Methylthioadenosine (MTA), the substrate of MTAP, accumulates as a result of MTAP deletion. Increased levels of MTA result in partial inhibition of the PRMT5 enzyme by competing with S-adenosylmethionine (SAM, the methyl donor for PRMT5 substrate) due to structural similarity. Cancer cell lines with MTAP-deletion exhibit profound sensitivity to PRMT5 inhibition, suggesting MTAPnull-selective PRMT5 inhibitors have the potential to treat patients with MTAP deficiency (Kryukov et al., 2016). We identified CTS3157 as an orally bioavailable small molecule MTA-cooperative PRMT5 inhibitor that binds to PRMT5-MTA complex and inhibits PRMT5 enzymatic activity. Cell-based assays revealed that CTS3157 demonstrated potent PRMT5 inhibition as evidenced by suppression of symmetric dimethylarginine (SDMA) and cell growth inhibitory activity for MTAP-deleted cell lines over isogenic MTAPWT cell lines. Moreover, CTS3157 series compounds exhibited strong cell growth inhibition in a diverse panel of MTAPnull human tumor cell lines across several lineages. In vivo, CTS3157 demonstrated potent antitumor response after once-daily oral administration in MTAP-deleted xenograft models. The anti-tumor activity is correlated with PRMT5 modulation as measured by reduced SDMA levels. At molecular level, PRMT5 inhibition by CTS3157 resulted in massive RNA splicing defects and differentially expressed genes involving key cellular activities in MTAPnull cells. In summary, MTAPnull-selective PRMT5 inhibitor CTS3157 showed strong and durable antitumor responses in vitro and in vivo in MTAP-deleted tumors across diverse lineages. CTS3157 is an effective and promising therapeutics against MTAP-deleted tumors.

Citation Format: Long Wang, Yilin Liu, Hui Shi, Yuanyuan Liu, Qiugeng Ouyang, Jiannan Guo, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS3157, a novel MTA-cooperative PRMT5 inhibitor for targeting MTAP-deleted human 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 6273.
Abstract 6279: CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human tumors
Authors: Shi Hui , Fu Xingnian , Ouyang Qiugeng , Huang Jiaxin , Wang Yiqin , Wang Youzhen , Xu Guoliang , Mi Yuan , Wu Haiping
Published: April 2023

Methylation of arginine residues by protein arginine methyltransferases (PRMTs) is involved in the regulation of fundamental cellular processes. Type I PRMTs are frequently overexpressed in a variety of human cancers and associated with poor prognosis. Knockout (KO) of Prmt1 in mice results in decreased asymmetric dimethylarginine (ADMA) on cellular proteins, together with increased monomethylarginine (MMA) and symmetric dimethylarginine (SDMA) (Dhar et al., 2013). A structure-based drug discovery effort led to the identification of CTS2190 that showed single-digit nanomolar enzymatic inhibitory activity on type I PRMTs. Here, we report the development and preclinical characterization of CTS2190, a potent, orally bioavailable small molecule type I PRMT inhibitor. CTS2190 demonstrated strong cellular proliferation inhibitory activity in a large, diverse panel of human hematological and solid tumor cell lines across several lineages. In vivo, oral CTS2190 administration once daily resulted in tumor regression in a variety of xenograft (both CDX and PDX) models across different lineages with good tolerance. The anti-tumor activity was dose-dependent and correlated with the inhibition of type I PRMT activity as measured by decrease in ADMA and increase in MMA. In summary, CTS2190 is a promising type I PRMT inhibitor and clinical trial is underway to explore the proof-of-concept anti-tumor benefit for patients.

Citation Format: Hui Shi, Xingnian Fu, Qiugeng Ouyang, Jiaxin Huang, Yiqin Wang, Youzhen Wang, Guoliang Xu, Yuan Mi, Haiping Wu. CTS2190, a next-generation epigenetic inhibitor for targeting type I PRMT deregulated human 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 6279.
Abstract 6282: EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML
Authors: Fraser Graeme , Sorlet Catherine , Parmentier Nicolas , Brunel Elodie , Hartiel Anne-France , Oukoloff Killian , Dutheuil Guillaume
Published: April 2023

METTL3 is the RNA methyltransferase predominantly responsible for the addition of N-6-methyladenosine (m6A), the most abundant modification to mRNA. The prevalence of m6A and the activity and expression of METTL3 have been linked to the appearance and progression of acute myeloid leukemia (AML)1. EPICS has discovered and optimized a small molecule inhibitor of METTL3 (“M3i”). M3i was shown to inhibit the enzymatic activity of METTL3 (IC50 = 2 nM, SPA assay) and inhibit the presence of intracellular m6A in a cell-based assay (IC50 = 8 nM, Calu6). The anti-proliferative effects of METTL3 was demonstrated in a spheroid model (NCIH-560, IC50 = 100 nM) as well as cell viability assays in various AML (Kasumi-1, IC50 = 30 nM; LEXF 41283, IC50 = 46 nM; MV-4-11, IC50 = 248 nM) and solid tumor (Calu6, IC50= 6 nM; Caov3, IC50 = 27 nM) cell lines. In vivo efficacy was evaluated in a disseminated xenograft model using established systemic MV-4-11-Luc-mCh-Puro2 in female NSG mice where M3i (30 mg/kg, i.p., QDx31 days) significantly (p<0.01, relative to vehicle control) inhibited cancer progression as measured by in-life imaging in addition to flow cytometry of hCD45+ cells in bone marrow, blood and spleen; M3i had minimal effects on hematopoiesis in this model with no significant changes in RBCs, WBCs and neutrophils, but an increase in platelets (measured by IDEXX). In an orthotopic, patient-derived xenograft model of AML (LEXF 41283, intratibial implantation, female NSG mice), M3i (30 mg/kg, i.p., QDx91 days) significantly prolonged survival (p<0.01, relative to vehicle control) with a commensurate absence of hCD45+ cells following compound treatment. These results confirm that the pharmacological inhibition of METTL3 is a viable strategy for the treatment of AML and support the additional exploration of the role of METTL3 inhibitors in alternate blood cancers as well as solid tumors.

Citation Format: Graeme Fraser, Catherine Sorlet, Nicolas Parmentier, Elodie Brunel, Anne-France Hartiel, Killian Oukoloff, Guillaume Dutheuil. EP102: Pharmacological inhibition of METTL3 arrests tumor progression and prolongs survival in CDX and PDX models of AML [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 6282.
Abstract 651: Revealing the role of lung cancer microbiota in the tumor progression
Authors: Riquelme Erick M. , Valdes Ivania , Aravena Carlos , Valencia Ilse , Mino Barbara , Carvajal Daniel , Martin Alberto
Published: April 2023

Lung cancer (LC) remains as the leading cause of death by cancer worldwide. In Chile, LC is the second cause of cancer-related deaths. Recently, studies in melanoma and non-small cell lung cancer (NSCLC) patients have highlighted the role of the gut microbiota as an important host factor in mediating the responses/resistance to immunotherapy, suggesting that bacteria present in the gut may modulate the immune response in these tumors. However, the role of extra-intestinal microbiota; bacteria living outside of the gut, in cancer pathogenesis and the response to anti-cancer therapies remains largely undetermined. Here we characterize the composition of intratumoral microbiota of NSCLC and seek to establish a functional relationship between it and the composition of the immune microenvironment and the clinicopathological characteristics of NSCLC patients. From the first 157 FFPE NSCLC samples, we extracted DNA from all collected samples, obtaining adequate material in quality and quantity to later be submitted for analysis to 16S sequencing. Using 16S rRNA gene sequencing, we assessed the general landscape of the NSCLC tumor microbiome, revealing the presence of large number of bacterial communities in the NSCLC tumor samples on the different histological subtypes analyzed. We have detected differences in alpha diversity in the histological subtypes studied. Even more interesting, we have detected significant differences in lung adenocarcinoma depending on the degree of histological differentiation, observing a decrease in proteobacteria and an enrichment of Bacteroidales, as cell differentiation is lost. Additionally, we identified taxonomic differences between differentiated and undifferentiated tumors. Differentiated tumors show enrichment in Akkermansia muciniphila and while undifferentiated tumors show enrichment in Actinobacter Corynebacterium. Suggesting that these taxa could contribute to maintaining a differentiated state or inducing cell dedifferentiation, respectively. Our results reveal the presence of a large number of bacterial communities in lung cancer samples in the different histological subtypes analyzed. Suggesting that these communities could play a key role in tumor differentiation and progression.

Citation Format: Erick M. Riquelme, Ivania Valdes, Carlos Aravena, Ilse Valencia, Barbara Mino, Daniel Carvajal, Alberto Martin. Revealing the role of lung cancer microbiota in the tumor progression [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 651.
Supplementary Table 2 from miRNA-302b Suppresses Human Hepatocellular Carcinoma by Targeting AKT2
Authors: Wang Lumin , Yao Jiayi , Zhang Xiaogang , Guo Bo , Le Xiaofeng , Cubberly Mark , Li Zongfang , Nan Kejun , Song Tusheng , Huang Chen
Published: April 2023

PDF file - 111K, The relationship between miR-302b levels and tumor stage.
Supplemental Table from Role of Rac1 Pathway in Epithelial-to-Mesenchymal Transition and Cancer Stem-like Cell Phenotypes in Gastric Adenocarcinoma
Authors: Yoon Changhwan , Cho Soo-Jeong , Chang Kevin K. , Park Do Joong , Ryeom Sandra W. , Yoon Sam S.
Published: April 2023

Clinical and pathologic characteristics of patients with gastric adenocarcinoma undergoing potentially curative surgical resection stratified by Rac 1 activity.
Supplementary Figures 1-7 from KRAS Activation in Gastric Adenocarcinoma Stimulates Epithelial-to-Mesenchymal Transition to Cancer Stem–Like Cells and Promotes Metastasis
Authors: Yoon Changhwan , Till Jacob , Cho Soo-Jeong , Chang Kevin K. , Lin Jian-xian , Huang Chang-ming , Ryeom Sandra , Yoon Sam S.
Published: April 2023

Supplementary Figure 1. KRAS knockdown inhibits EMT in tumor organoids from a GA GEMM. Supplementary Figure 2. Oncogenic KRAS promotes EMT and acquisition of CSC phenotypes in gastric epithelial cells. Supplementary Figure 3. RTK-RAS pathway controls CSC phenotypes in human GA-derived spheroids. Supplementary Figure 4. MEK inhibition of the RTK-RAS pathway. Supplementary Figure 5. CD44(+) vs. CD44(-) spheroid cells. Supplementary Figure 6. Chemoresistance. Supplementary Figure 7. KRAS knockdown inhibits EMT and infiltrative behavior of human GA-derived cells.