bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1886: BRY812, an anti-LIV-1 antibody drug conjugate with novel conjugation method for cancer therapeutics
Authors: Zhao Xiaobei , Zhu Jie , Zhou Yaqiong , Li Jing , Nie Lei , Wang Haibin , Chen Gang 
Published: March 2024

Abstract
LIV-1, also known as SLC39A6 or ZIP6, belongs to the zinc transporter family and was initially identified as an estrogen-inducible gene in breast cancer. Immunohistochemical (IHC) analysis have revealed escalated LIV-1 expression in estrogen receptor-positive (ER+), hormone-treated tumors (both primary and metastatic sites) as well as ER-/PR-/Her2- (triple-negative) breast cancers. Notably, healthy human tissues exhibit limited LIV-1 expression, primarily in hormone regulated organs (prostate, uterus, and breast). The escalated expression of LIV-1 in breast and prostate cancer, as well as melanoma and other tumors, positions LIV-1 as an excellent target for ADC therapeutics.
BRY812 is a monomethyl auristatin E (MMAE)-conjugated humanized IgG1 ADC against LIV-1. With Bioray’s irreversible conjugation method CysLinkTM, BRY812 enables superior in vivo stability and eliminates off-target payload migration. The PK studies in rat and monkey demonstrated that the free MMAE released from ADC is 1 to 2 logs lower compared with approved ADCs prepared by the standard conjugation method. BRY812 is well tolerated in cynomolgus monkeys with repeated doses. With best-in-class anti-tumor efficacy in various models, BRY812 demonstrated a wider therapeutic window for cancer treatment. BRY812 is currently in Phase Ia dose escalation stage clinical trial to explore the maximum tolerate dosage (MTD) from 0.25 to 3.6 mg/kg Q3W in patients with advanced malignancies.
Citation Format: Xiaobei Zhao, Jie Zhu, Yaqiong Zhou, Jing Li, Lei Nie, Haibin Wang, Gang Chen. BRY812, an anti-LIV-1 antibody drug conjugate with novel conjugation method for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1886.
Abstract 1898: LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers
Authors: Fitzgerald Daniel P. , Doan Duc N. , Peacock Riley B. , Kahan Shannon M. , Lomash Suvendu , Slocum Stephen , Jung Kwang Hwa , Oh Hwanhee , Meza Ingrid , Manzanarez Yanira , Selvam Shanmugam , Flies Dallas B. , Chung Chul-Woong , Langermann Sol 
Published: March 2024

Abstract
The B7 family protein B7-H4 is highly expressed on a range of solid tumors including breast, ovarian, and endometrial cancers, where it may play a role in immune evasion. In non-cancerous tissues, B7-H4 expression is limited, suggesting it may be a potential target for an antibody drug conjugate (ADC). LNCB74 is a human IgG1 antibody conjugated to the potent microtubule disrupting payload monomethyl auristatin E (MMAE) with a drug-to-antibody ratio of 4 (DAR4). The ADC employs a highly selective B7-H4 antibody based upon NextCure’s expertise in B7-H4 tumor biology coupled with a glucuronidase-cleavable, site-specific linkage to an engineered cysteine in the antibody light chain via LegoChem Biosciences’ ConjuAllTM technology. This improves the safety profile and therapeutic index of the agent by a) increasing stability in circulation, b) selectively releasing payload in tumor cells, and c) reducing payload release in off-target cells. LNCB74 was further engineered with a “LALA”-mutant Fc region to minimize uptake and toxicity to immune cells. In a nonhuman primate (NHP) toxicity study, LNCB74 was well tolerated for repeat dosing and provides evidence for a superior safety profile without noticeable side effects. LNCB74 is rapidly internalized by B7-H4-expressing tumor cells, and demonstrates potent, target-specific cytotoxicity on multiple cancer cell lines. In vivo studies demonstrate a strong bystander effect following a single dose administration of LNCB74. A rapid and durable anti-tumor response has been demonstrated in multiple cell-line derived (CDX) and patient-derived xenograft (PDX) tumor models. In summary, LNCB74 is a promising ADC enabling specific targeting of B7-H4 positive cancers across a spectrum of indications.
Citation Format: Daniel P. Fitzgerald, Duc N. Doan, Riley B. Peacock, Shannon M. Kahan, Suvendu Lomash, Stephen Slocum, Kwang Hwa Jung, Hwanhee Oh, Ingrid Meza, Yanira Manzanarez, Shanmugam Selvam, Dallas B. Flies, Chul-Woong Chung, Sol Langermann. LNCB74 is a potent and safe next-generation antibody-drug-conjugate utilizing a cancer selective linker for the treatment of B7-H4 expressing cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1898.
Abstract 1914: Amivantamab efficacy in wildtype EGFR NSCLC tumors correlates with levels of ligand expression
Authors: Rivera-Soto Ricardo , Henley Benjamin , Pulgar Marian , Lehman-Tenuto Stacey , Gupta Himanshu , Weindorfer Megan , Vijayaraghavan Smruthi , Yao Tsun-Wen , Laquerre Sylvie , Moores Sheri 
Published: March 2024

Abstract
Amivantamab (RYBREVANT™) is an FDA-approved, low-fucose IgG1 bispecific antibody targeting EGF and Met receptor tyrosine kinases, with proven clinical activity against EGFR mutant non-small cell lung cancer (NSCLC). Preclinical studies demonstrated that three context-dependent mechanisms of action (MOA) contribute to amivantamab efficacy: immune cell-mediated killing by antibody-dependent cellular cytotoxicity and trogocytosis, receptor internalization and degradation, and inhibition of ligand binding to both EGF and Met receptors. In tumors lacking known cancer-driver genetic aberrations, ligand binding to wildtype EGFR (EGFRWT) and/or MetWT may activate downstream signaling pathways, inducing pro-tumorigenic processes. Among the EGFR ligands, we demonstrated that amphiregulin (AREG) is highly expressed in EGFRWT NSCLC primary tumors, with significantly higher circulating protein levels in NSCLC patients than in healthy volunteers, and induces EGFR phosphorylation, promoting downstream signaling and increasing cell proliferation. Importantly, treatment of AREG-stimulated EGFRWT cells/tumors with amivantamab, or an AREG-targeting antibody, inhibits ligand-induced signaling and cell/tumor proliferation/growth. Across 10 EGFRWT NSCLC patient-derived xenograft mouse models, amivantamab efficacy correlated with AREG RNA levels, suggesting AREG as a potential predictive marker for amivantamab activity in this population. Interestingly, in these xenograft models, amivantamab anti-tumor activity was independent of amivantamab's Fc engagement with immune cells, suggesting that, in this context, the amivantamab’s ligand-blocking function is sufficient for its efficacy. Juxtaposedly, we previously demonstrated that low fucose amivantamab, active Fc domain, was necessary for maximal anti-tumor activity against tumors with EGFR or Met activating mutations. Altogether, these results demonstrated amivantamab context-dependent MOA for efficacy. In conclusion, these data 1) highlight EGFR ligand AREG as a driver of tumor growth in some EGFRWT NSCLC models, 2) illustrate the preclinical efficacy of amivantamab in ligand-driven EGFRWT NSCLC, and 3) identify AREG as a potential predictive biomarker for amivantamab against anti-EGFRWT therapies.
Citation Format: Ricardo Rivera-Soto, Benjamin Henley, Marian Pulgar, Stacey Lehman-Tenuto, Himanshu Gupta, Megan Weindorfer, Smruthi Vijayaraghavan, Tsun-Wen Yao, Sylvie Laquerre, Sheri Moores. Amivantamab efficacy in wildtype EGFR NSCLC tumors correlates with levels of ligand expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1914.
Abstract 1941: AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer
Authors: Morimoto Kenji , Yamada Tadaaki , Hirai Soichi , Katayama Yuki , Kunimasa Kei , Sasaki Takaaki , Nishida Makoto , Watanabe Satoshi , Shiotsu Shinsuke , Uehara Hisanori , Takayama Koichi 
Published: March 2024

Abstract
Background: KRAS is the most frequent targetable oncogene in non-small cell lung cancer (NSCLC). Recently, novel KRAS inhibitor have been clinically developed for treatment of KRAS G12C-mutated NSCLC patients. However, it is difficult to achieve complete remission of tumor. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. In this study, we focused on the mechanisms underlying adaptive resistance to KRAS G12C inhibitors and therapeutic strategies required to overcome them.
Methods: We used KRAS G12C-mutated NSCLC cell lines to evaluate the adaptive response to KRAS G12C inhibitors in vitro and in vivo. We also investigated the correlation between AXL expression in pre-treated tumors and clinical outcomes with sotorasib for KRAS G12C-mutated NSCLC patients.
Results: We revealed that AXL signaling leads to the adaptive resistance to KRAS G12C inhibitors in KRAS-G12C mutated NSCLC, activation of which is induced by GAS6 production via transcriptional coactivator YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or the combination after acquired resistance to KRAS G12C inhibitor. AXL was highly expressed in clinical specimens of KRAS G12C-mutated lung cancers and its high expression was associated with a low treatment response to sotorasib.
Conclusions: These results indicated pivotal roles for AXL activation and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.
Citation Format: Kenji Morimoto, Tadaaki Yamada, Soichi Hirai, Yuki Katayama, Kei Kunimasa, Takaaki Sasaki, Makoto Nishida, Satoshi Watanabe, Shinsuke Shiotsu, Hisanori Uehara, Koichi Takayama. AXL activation promotes adaptive resistance to KRAS-G12C inhibitors in KRAS-G12C-mutated non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1941.
Abstract 1965: 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid tumors
Authors: Liu-Chen Susan S. , Lin Jufang , Hu Jingyu , Liu Yanchao , Zhang Weibo , Zhang Zhixiong , Ding Yan , Liu Jinqiu , Chen Kevin , Hu Shaojing 
Published: March 2024

Abstract
FDA-approved pan-FGFR inhibitors bring encouraging results in solid tumors. However, resistance mechanisms and side effect profiles may limit their clinical utility. We designed 3HP-2827, a highly selective and potent small molecule inhibitor of FGFR2, to treat solid tumors harboring FGFR2 alterations, including amplifications, mutations, and fusions to overcome these limitations. 3HP-2827 inhibits FGFR2 enzyme activity with more than 1623-fold selectivity over FGFR1 and FGFR3. 3HP-2827 inhibits cell proliferation with IC50 &lt;10 nM and 30 nM in FGFR2 amplified and FGFR2-mutant cancer cell lines, respectively. 3HP-2827 demonstrates high kinome selectivity for FGFR2 against a panel of 485 human kinases, resulting in 90.1% inhibition of FGFR2, and no other kinases showed greater than 75% inhibition. 3HP-2827 leads only modest activity at 10 µM against PDE4D2 and LCK in 44 distinct common adverse drug reaction targets, supporting its high degree of safety. 3HP-2827 also demonstrates a dose-dependent inhibition of phosphorylation of FGFR2 and FGFR2 signaling pathway nodes, including ERK and AKT, in the FGFR2-dependent cancer cell line. In vivo, 3HP-2827 demonstrates potent antitumor activity in cell- and patient-derived xenograft mouse models, including FGFR2-amplified gastric cancer, FGFR2-mutant (N549K) endometrial cancer, FGFR2 fusion ICC and gastric cancers. Strikingly, 3HP-2827 demonstrates superior activity in patient-derived ICC and gastric cancer, cell-derived endometrial cancer (CDX) in tumor and pFGFR2 inhibitions. In the ICC PDX model, 3HP-2827 also induces the regression of pemigatinib-resistant tumors. 3HP-2827 is well tolerated in the toxicology studies, and no hyperphosphatemia or tissue mineralization is observed at 150 mg/kg/kg/day in rats and 120 mg/kg/day in dogs. The data support that 3HP-2827, a potential to be a best-in-class selective FGFR2 inhibitor, will be studying clinically at the beginning of 2024.
Citation Format: Susan S. Liu-Chen, Jufang Lin, Jingyu Hu, Yanchao Liu, Weibo Zhang, Zhixiong Zhang, Yan Ding, Jinqiu Liu, Kevin Chen, Shaojing Hu. 3HP-2827-high selective inhibitor of FGFR2, a best-in-class therapy for FGFR2-driven solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1965.
Abstract 198: Selective targeting of endothelial mTORC1 reduces transendothelial fatty acid delivery to improve anti-tumor immunity and suppress metastatic outgrowth
Authors: Edwards Deanna N. , Wang Shan , Song Wenqiang , Kim Laura C. , Hwang Yoonha , Chen Jin 
Published: March 2024

Abstract
Tumor metastasis requires sufficient nutrients to support outgrowth of disseminated tumor cells. Cancer cells utilize fatty acids as a key source of energy and biomass, but these nutrients impair the cytotoxic activities of T cells, serving to support metastatic progression. Blood is a rich source of fatty acids, but the vascular endothelium serves as a barrier to limit access to the surrounding tumor tissue. However, it is unclear how long-chain fatty acid delivery to early metastatic tumors is regulated. Here, we report that endothelial mTORC1 promotes transport of fatty acids into developing metastatic tumors, leading to reduced anti-tumor immune responses and improved outgrowth. Using a murine model of metastatic outgrowth in the lung, tumor burden was significantly reduced upon targeted deletion of Raptor, an essential component of the mTORC1 complex, in endothelial cells (RptorECKO). We employed a multifaceted approach using metabolomics, transcriptomics, and molecular assays to identify a Raptor/mTORC1-mediated mechanism of transendothelial fatty acid transport via RAB and CLSTN1 cargo trafficking. In vivo uptake of a fluorescent palmitic acid analog in tumor cells and T cells was reduced in RptorECKO lung metastatic tumors, which correlated with improved markers of cytotoxicity. Combination of low-dose RAD001/everolimus, which selectively inhibits mTORC1 in endothelial cells, with anti-PD1 reduces metastatic disease and impairs long-chain fatty acid uptake in T cells, corresponding to improved anti-tumor immunity. These findings describe a novel mechanism of transendothelial fatty acid transportation during metastatic outgrowth, supporting future development of therapeutic strategies to target endothelial mTORC1 activity.
Citation Format: Deanna N. Edwards, Shan Wang, Wenqiang Song, Laura C. Kim, Yoonha Hwang, Jin Chen. Selective targeting of endothelial mTORC1 reduces transendothelial fatty acid delivery to improve anti-tumor immunity and suppress metastatic outgrowth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 198.
Abstract 1988: Mass spectrometry profiling identifies ENO2 as a driver of lenvatinib resistance in hepatocellular carcinoma
Authors: Kim Sukbum , Loh Jia-Jian , Yu Huajian , Man Ki-Fong , Ng Kai-Yu , Lee Terence Kin-Wah , Chung Clive Yik-Sham , Ma Stephanie 
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, and lenvatinib is a multi-kinase inhibitor approved by the FDA as a first-line drug for advanced HCC since 2018. Lenvatinib demonstrated antitumor activity with a higher objective response rate, longer progression-free survival, and time to progression in a non-inferiority trial compared with sorafenib. However, the clinical benefits of lenvatinib remain limited as acquired resistance to lenvatinib during HCC treatment is inevitable. This highlights the need to understand the molecular mechanisms of lenvatinib resistance and to explore new therapeutic approaches to overcome this resistance. Tumor lineage plasticity, a recognized hallmark of cancer, is a phenomenon in which tumor cells dedifferentiate into a more stemness state to attain cellular plasticity, enabling them to evade targeted therapeutic interventions. However, the mechanism by which cellular plasticity contributes to lenvatinib resistance remains elusive. In this study, we employed proteomic mass spectrometry to investigate altered proteins in two pairs of parental lenvatinib-sensitive and their corresponding trained lenvatinib-resistant HCC cell lines. This analysis revealed that upregulation of enolase 2 (ENO2), a glycolytic enzyme that catalyzes the dehydration and conversion of 2-phosphoglycerate to phosphoenolpyruvate, is a critical contributor. ENO2 upregulation is frequently observed in HCC and is strongly correlated with aggressive clinical features, including poor survival, advanced tumor stage, and poor differentiation status. We further showed that ENO2 upregulation in HCC is positively correlated with stemness and hepatic progenitor marker signatures, as well as hypoxia, and subsequently demonstrated that ENO2 is regulated by hypoxia/HIF-1α, with hypoxia response element sequences located in the ENO2 promoter region. Research is underway to investigate the functional role and underlying molecular mechanisms associated with ENO2-driven lenvatinib resistance and cellular plasticity in HCC.
Citation Format: Sukbum Kim, Jia-Jian Loh, Huajian Yu, Ki-Fong Man, Kai-Yu Ng, Terence Kin-Wah Lee, Clive Yik-Sham Chung, Stephanie Ma. Mass spectrometry profiling identifies ENO2 as a driver of lenvatinib resistance in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1988.
Abstract 1990: TIP60-mediated acetylation of ΔNp63α is associated with cisplatin resistance
Authors: Hira Akshay , Zhang Jin , Kemp Mike , Kadakia Madhavi P. 
Published: March 2024

Abstract
The chemotherapeutic drug Cisplatin is often used to treat squamous cell carcinoma (SCC) patients, but low response rates and disease recurrence are common. About 5.4 million basal and squamous cell skin cancers are diagnosed each year in the US. ΔNp63α, a member of the p53 family of transcription factors, is overexpressed and considered oncogenic in non-melanoma skin cancer where it regulates cell survival, promotes proliferation, and inhibits cell apoptosis. ΔNp63α has also been shown to promote resistance to cisplatin by orchestrating the transcriptional regulation of several DNA damage response (DDR) genes. Our previous study showed that the histone acetyltransferase (HAT) TIP60 promotes SCC proliferation by positively regulating ΔNp63α protein levels in a manner reliant on the catalytic activity of TIP60. This observation suggested that TIP60 may contribute to the failure of platinum-based drugs in SCC and led us to hypothesize that TIP60-mediated acetylation of ΔNp63α regulates its stability and transcriptional activity to promote chemoresistance. We found that TIP60 levels positively correlated with ΔNp63α stability, protein levels, and cisplatin resistance. Further, silencing endogenous TIP60 led to a decrease in ΔNp63α transcript and protein levels in multiple cisplatin resistant SCC cell lines. Further, stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, whereas loss of ΔNp63α or TIP60 induced G2/M arrest, increased cell death, and sensitized cells to cisplatin. Additionally, pharmacological inhibition of TIP60 reduced acetylation of ΔNp63α, decreased colony formation, and sensitized resistant cells to cisplatin. Finally, we demonstrated that ΔNp63α and TIP60 levels positively correlated with DNA repair capacity and negatively correlated with cisplatin-DNA adduct formation. Silencing of either TIP60 or ΔNp63α intensified cisplatin-DNA adduct formation and significantly reduced the expression of drug efflux transporters. Taken together, our data indicate that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance in SCC. Our findings suggest that the inhibition of TIP60 may be therapeutically advantageous in overcoming cisplatin resistance in SCC and other epithelial cancers.
Citation Format: Akshay Hira, Jin Zhang, Mike Kemp, Madhavi P. Kadakia. TIP60-mediated acetylation of ΔNp63α is associated with cisplatin resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1990.
Abstract 2014: Tumor glycosylation impacts the efficacy of HER2 targeting therapies
Authors: Ruiz-Saenz Ana , Vincken Roos , Wolf Denise , Steri Veronica , Veer Laura van't , Martens John , Huylebroeck Danny , Moasser Mark M. 
Published: March 2024

Abstract
Cancer progression remains a major obstacle to the successful treatment of cancer. In HER2+ breast cancer, targeting therapies against HER2 have revolutionized the treatment landscape. However, predictive factors for response are largely unknown and a significant number of patients develop resistance. An extensive body of work has revealed a plethora of mechanisms of resistance. However, a key aspect of cancer cells has been largely overlooked: their aberrant glycosylation profile. Aberrant glycosylation of proteins is a hallmark in cancer and has been linked to multiple processes such as invasion, angiogenesis and modulation of the immune response. Yet the influence of altered glycosylation on the efficacy of HER2-targeted therapies remains unknown. Therefore, here, we address this question using clinical data, 3D co-culture systems and advanced live microscopy. Bioinformatics analysis of SPY-2 clinical trial data reveals an association of specific glycogenes with response to HER2-targeting therapies in breast cancer patients. We validated these findings in resistance cell models generated in-vitro and in-vivo using gain and loss of function assays. Furthermore, to provide a more relevant cell model system, we implement the use of 3D co-cultures of cancer spheroids and immune cells. Thus, our research addresses a largely unexplored area in cancer biology combining clinical data from tumor biopsies, trastuzumab-resistant cancer cell models and, live imaging of 3D heterotypic cultures. This work holds the potential to identify new markers of response to therapies and highlights the importance of the interplay of cancer cells and their microenvironment on the efficacy of current treatments.
Citation Format: Ana Ruiz-Saenz, Roos Vincken, Denise Wolf, Veronica Steri, Laura van't Veer, John Martens, Danny Huylebroeck, Mark M. Moasser. Tumor glycosylation impacts the efficacy of HER2 targeting therapies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2014.