bluuebunny/crossref_metadata_2025 huggingface dataset:
Supplementary Figure 1 from Suppression of Tumor Cell Lactate-generating Signaling Pathways Eradicates Murine PTEN/p53-deficient Aggressive-variant Prostate Cancer via Macrophage Phagocytosis
Authors: Chaudagar Kiranj , Hieromnimon Hanna M. , Kelley Anne , Labadie Brian , Shafran Jordan , Rameshbabu Srikrishnan , Drovetsky Catherine , Bynoe Kaela , Solanki Ani , Markiewicz Erica , Fan Xiaobing , Loda Massimo , Patnaik Akash
Published: December 2023

Persistent MEK signaling in PTEN/p53-deficient GEM tumors resistant to PI3Ki monotherapy
Supp Fig 8 from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

Supp Figure 8. Comparison of outcomes in ATM missense vs truncating mutations vs wild-type tumors in the FH-FMI CGDB cohort.
Supp Fig 4 from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

Supp Figure 4. ATM variants, protein and mRNA expression.
Supp Fig 3 from ATM Mutations Associate with Distinct Co-Mutational Patterns and Therapeutic Vulnerabilities in NSCLC
Authors: Vokes Natalie I. , Galan Cobo Ana , Fernandez-Chas Margarita , Molkentine David , Treviño Santiago , Druker Vitaly , Qian Yu , Patel Sonia , Schmidt Stephanie , Hong Lingzhi , Lewis Jeff , Rinsurongkawong Waree , Rinsurongkawong Vadeerat , Lee J. Jack , Negrao Marcelo V. , Gibbons Don L. , Vaporciyan Ara , Le Xiuning , Wu Jia , Zhang Jianjun , Rigney Una , Iyer Sonia , Dean Emma , Heymach John V.
Published: December 2023

Supp Figure 3. ATM co-mutation enrichment analyses within cohorts, stratified by KRAS mutation status.
Supplementary Table S2 from Potential of Fecal Microbiota Transplantation to Prevent Acute GVHD: Analysis from a Phase II Trial
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef Ur , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: December 2023

Representativeness of study participants
Supplementary Table S1 from Potential of Fecal Microbiota Transplantation to Prevent Acute GVHD: Analysis from a Phase II Trial
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef Ur , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: December 2023

Baseline patient characteristics in the FMT and placebo arms
Supplementary Data 1 from Tumor-Infiltrating Normal B Cells Revealed by Immunoglobulin Repertoire Clonotype Analysis Are Highly Prognostic and Crucial for Antitumor Immune Responses in DLBCL
Authors: Xu-Monette Zijun Y. , Li Yong , Snyder Thomas , Yu Tiantian , Lu Tingxun , Tzankov Alexandar , Visco Carlo , Bhagat Govind , Qian Wenbin , Dybkaer Karen , Chiu April , Tam Wayne , Zu Youli , Hsi Eric D. , Hagemeister Fredrick B. , Wang Yingjun , Go Heounjeong , Ponzoni Maurilio , Ferreri Andrés J.M. , Møller Michael B. , Parsons Benjamin M. , Fan Xiangshan , van Krieken J. Han , Piris Miguel A. , Winter Jane N. , Au Qingyan , Kirsch Ilan , Zhang Mingzhi , Shaughnessy John , Xu Bing , Young Ken H.
Published: December 2023

Supplementary Methods, Tables 1-11, and Figures 1-16
Table S2 from A Prospective Study Exploring the Safety and Efficacy of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma and High Tumor Burden: The LAUNCH Study
Authors: Kobayashi Kazufumi , Ogasawara Sadahisa , Maruta Susumu , Okubo Tomomi , Itokawa Norio , Haga Yuki , Seko Yuya , Moriguchi Michihisa , Watanabe Shunji , Shiko Yuki , Takatsuka Hirokazu , Kanzaki Hiroaki , Koroki Keisuke , Inoue Masanori , Nakamura Masato , Kiyono Soichiro , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Inaba Yosuke , Ikeda Masafumi , Okabe Shinichiro , Morimoto Naoki , Itoh Yoshito , Nakamura Kazuyoshi , Ito Kenji , Azemoto Ryosaku , Atsukawa Masanori , Itobayashi Ei , Kato Naoya
Published: December 2023

Adverse events during the study period
Figure S1 from A Prospective Study Exploring the Safety and Efficacy of Lenvatinib for Patients with Advanced Hepatocellular Carcinoma and High Tumor Burden: The LAUNCH Study
Authors: Kobayashi Kazufumi , Ogasawara Sadahisa , Maruta Susumu , Okubo Tomomi , Itokawa Norio , Haga Yuki , Seko Yuya , Moriguchi Michihisa , Watanabe Shunji , Shiko Yuki , Takatsuka Hirokazu , Kanzaki Hiroaki , Koroki Keisuke , Inoue Masanori , Nakamura Masato , Kiyono Soichiro , Kanogawa Naoya , Kondo Takayuki , Suzuki Eiichiro , Ooka Yoshihiko , Nakamoto Shingo , Inaba Yosuke , Ikeda Masafumi , Okabe Shinichiro , Morimoto Naoki , Itoh Yoshito , Nakamura Kazuyoshi , Ito Kenji , Azemoto Ryosaku , Atsukawa Masanori , Itobayashi Ei , Kato Naoya
Published: December 2023

Patient flow of the LAUNCH study
New T-Cell Therapies for Brain Metastasis, CD133 in the Driver's Seat
Authors: Sloan Anthony R. , Thapliyal Mihika , Lathia Justin D.
Published: December 2023

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized cancer therapy for some advanced cancers, but success is predicated on identifying the correct cell surface target. In a recent article, the authors leveraged the cancer stem cell surface antigen CD133 to develop a CAR-T therapy for brain metastasis.

See related article by Kieliszek et al., p. 554
Abstract A001: Mapping the interaction between C-type lectin domain group 14A and Multimerin 2
Authors: Baber Aleen , Birmingham Victoria L , Bicknell Roy , Morrison Philip R
Published: December 2023

Introduction: Understanding the molecular basis of protein-protein interactions involved in the regulation of angiogenesis enhances our understanding of cancer pathogenesis and enables the development of novel anti-cancer therapies. In this study, we focused on the transmembrane spanning glycoprotein C-type lectin domain group 14A (CLEC14A), which is exclusively expressed on the tumor endothelium and is important in regulating tumor growth. CLEC14A promotes endothelial tube formation and migration in vitro, in addition tumor growth is retarded in CLEC14A knockout mice. CLEC14A, through its N-terminal C-type lectin domain (CTLD) interacts with the extracellular matrix protein Multimerin 2 (MMRN2) and heparan sulfate proteoglycans. Administration of antibodies which block the CLEC14A-MMRN2 interaction decreases tumor growth in vivo indicating the importance of this interaction, however the biological significance of CLEC14A’s binding to heparan sulfate proteoglycans is not known.

Aims: The purpose of this study was to identify the area and key residues on CLEC14A which interact directly with MMRN2. Mapping the CLEC14A-MMRN2 interface would enable the design of small molecule inhibitors of this interaction, a potential anti-cancer strategy.

Methods: We employed the Alpha fold predictive modelling algorithm to analyze the predicted structure of CLEC14A. Solvent-facing residues within a previously identified critical loop region were mutated to alanine and binding to MMRN2 was determined. Flow cytometry was used to assess the cell surface expression of these CLEC14A mutants, and far western blotting was employed to determine their capacity to bind MMRN2. Furthermore, we studied whether these mutants interacted with heparin-bound agarose beads in pulldown assays.

Results: The alanine-scanning approach resulted in the identification of specific residues of CLEC14A which directly interacted with MMRN2. Furthermore, we identified the epitope on CLEC14A for a biologically active antibody previously reported to block the CLEC14A-MMRN2 interaction. Additionally, we identified critical residues that are essential for cell surface trafficking of CLEC14A. Importantly, the CLEC14A mutants that do not bind to MMRN2 retain their capacity to bind heparin.

Conclusion: By leveraging predictive modelling software, we have characterized the molecular interaction between CLEC14A and MMRN2. Our findings may inform anti-angiogenesis drug design in the future.

Citation Format: Aleen Baber, Victoria L Birmingham, Roy Bicknell, Philip R Morrison. Mapping the interaction between C-type lectin domain group 14A and Multimerin 2 [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A001.
Abstract A019: eIF4A and PDCD4 expression in TNBC underlies sensitivity to natural product translation inhibitor
Authors: Subramanian Alagu , Xue Haoran , Hull Kenneth G , Romo Daniel , Taube Joseph
Published: December 2023

Despite recent advances in immunotherapy and adjuvant-therapy, resistance to cancer therapeutics is common and requires novel approaches. Moreover, highly aggressive triple-negative breast cancers lack effective targeted treatments. Deregulation of translation factors is associated with the increased proliferation of TNBC cells, heightened CSC activity, and poor patient outcomes. Thus targeting translation regulatory factors upregulated in TNBC is a promising approach to developing novel treatments. Pateamine A (PatA), a natural marine macrodiolide product, inhibits RNA cap-dependent translation by binding and sequestering the eukaryotic translation initiation factor eIF4A. eIF4A promotes the translation of polypurine-rich mRNA sequences, which are enriched within breast cancer oncogenes. Here we report the anticancer efficacy of novel PatA analogs we have synthesized against breast cancer cell lines. The PatA analogs exhibited selective cytotoxicity to breast and colorectal cancers compared to non-cancerous cells measured by Cell Titer-Blue viability studies. Novel analogs show greater antiproliferative potency against models of triple-negative than against human mammary epithelial cells (HMLE). To further elucidate eIF4A as a molecular target, we conducted analyses of patient tissue samples in the Cancer Genome Atlas (TCGA). Our analyses reveal the overexpression of eIF4A in tumor tissues compared to normal tissues and gene correlation studies reveal the upregulation of key co-expressed tumor drivers including beta-catenin, fibronectin, and epithelial-to-mesenchymal transition (EMT) markers such as SNAIL and SLUG. Further analyses show a downregulation of tumor suppressor protein PDCD4, an endogenous inhibitor of eIF4A, in cancer tissues. We have generated eIF4A shRNA knockdown and PDCD4 shRNA knockdown cell lines to uncover the eIF4A-PDCD4 regulatory axis across breast adenocarcinoma and colorectal adenocarcinoma cell types. We show that the loss of eIF4A attenuates the mesenchymal and stem-like phenotype of breast cancer stem cells revealed by phenotypic assays. Our results suggest that targeting translation initiator eIF4A is an effective approach against highly proliferative and metastatic breast cancer types. The presented findings underscore the potential of eIF4A as a promising molecular target and supports translational control as a viable approach against aggressive cancers.

Citation Format: Alagu Subramanian, Haoran Xue, Kenneth G Hull, Daniel Romo, Joseph Taube. eIF4A and PDCD4 expression in TNBC underlies sensitivity to natural product translation inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A019.
Abstract A025: Cytostatic effects and expression modulations in cell cycle genes by a 3rd generation alkyl-phospholipid (erufosine) in liver and lung cancer cells
Authors: Pervaiz Asim , Nasim Marriyam , Shafiq Nazakat , Berger Martin R.
Published: December 2023

Introduction: Alkyl-phospholipids (ALPs) are a family of compounds that have affinity to cell membranes and have demonstrated antineoplastic potential. Erufosine is a 3rd generation ALP that can be injected intravenously for its long (22-carbon) chain with a cis-13,14 double bond. Erufosine, like other ALPs, causes changes in the lipid rafts of the cell membrane and exerts its anticancer effects through cytotoxic and cytostatic mechanisms. In this study, intentions were to investigate erufosine mediated cytostatic effects in liver and lung cancer cells at functional and molecular levels.

Materials and Methods: Liver (HepG2) and lung (H1299) cancer cell lines were exposed to various concentrations of erufosine (1.56-50µM) and resulting anti-proliferative effects were monitored via MTT dye reduction assay. Cytostatic effects of erufosine on the two cancer cell lines were investigated via propidium iodide-based DNA staining and FACS analysis. A real time PCR based panel was used to decipher the impact of erufosine exposure on 84 cell cycle related genes in the two cancer cell lines. Fold changes were identified via the Livak method while untreated cells were used as controls.

Results: Erufosine induced the anti-proliferative effects in both cancer cell lines, however, lung cancer cells were more sensitive (IC50: 6.25µM) as compared to liver cancer cells (IC50: 33µM). The compound induced a comparable cell cycle arrest in S phase in the cancer cell lines as reflected by more accumulation of the cells in this particular phase. Exposure with erufosine (IC50/48 hours) de-regulated the cell cycle related genes in both cancer cell lines. Again, the lung cancer cells were more responsive in comparison to liver cancer cells as reflected by a substantial de-regulation (≥2fold) of 35/84 (42%) and 13/84 (15%) genes, respectively.  

Conclusion: The findings of this study confirmed erufosine mediated anti-proliferative and cytostatic effects in the liver and lung cancer cells. Furthermore, the compound induced substantial alterations in cell cycle related genes in the two cancer cell lines. Present findings foster further research to investigate the antineoplastic effects induced by erufosine in liver and lung cancer cells to support its clinical utilization.

Citation Format: Asim Pervaiz, Marriyam Nasim, Nazakat Shafiq, Martin R. Berger. Cytostatic effects and expression modulations in cell cycle genes by a 3rd generation alkyl-phospholipid (erufosine) in liver and lung cancer cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A025.
Abstract B085: Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer
Authors: Taya Marwa , Merenbakh-Lamin Keren , Zubkov Asia , Honig Zohar , Mayer Ori , Shomron Noam , Wolf Ido , Rubinek Tami
Published: December 2023

Purpose: All patients with metastatic breast cancer (BC) expressing estrogen receptor α (ESR1) will eventually develop resistance to endocrine therapies. In up to 40% of cases, this resistance is caused by activating mutations in the ligand-binding domain (LBD) of ESR1. Clinical evidence suggests adverse outcomes for these patients. Our hypothesis was that ESR1 mutations may confer resistance to subsequent treatment lines, specifically chemotherapy.

Experimental Design: MCF-7 cells harboring ESR1 mutations (Y537S and D538G) were used to characterize proliferation, apoptosis, and tumor response to chemotherapy in vivo. JNK/c-Jun/MDR1 pathway was studied using qRT-PCR, western-blot, gene-reporter, ChIP assays and pharmacological inhibition.

Results: Our results revealed that the mutated-ER (mut-ER) cells displayed relative chemoresistance, demonstrated by higher viability and reduced apoptosis. In vivo mouse model confirmed these findings. To elucidate the underlying mechanism, we examined MDR1 expression and JNK pathway activity. We observed elevated MDR1 expression in mut-ER cells, which was also reflected in clinical BC samples. Additionally, increased occupancy of the MDR1 promoter by c-Jun was observed in mut-ER cells. Importantly, inhibition of the JNK pathway resulted in decreased MDR1 expression, particularly in D538G cells. Moreover, JNK inhibition increased apoptosis and reduced viability in all cells, with a more pronounced effect in D538G cells.

Conclusions: Taken together, our data indicate that ESR1 mutations confer chemoresistance in BC through the activation of the JNK/MDR1 axis. These findings suggest that targeting this pathway could be a potential strategy for novel treatments aimed at restoring chemotherapy sensitivity and improving outcomes for patients with metastatic BC.

Citation Format: Marwa Taya, Keren Merenbakh-Lamin, Asia Zubkov, Zohar Honig, Ori Mayer, Noam Shomron, Ido Wolf, Tami Rubinek. Beyond endocrine resistance: estrogen receptor (ESR1) activating mutations mediate chemotherapy resistance through the JNK/c-Jun MDR1 pathway in breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B085.
Abstract B089: MUC1-C is a common driver of acquired osimertinb resistance in NSCLC
Authors: Haratake Naoki , Ozawa Hiroki , Morimoto Yoshihiro , Yamashita Nami , Daimon Tatsuaki , Bhattacharya Atrayee , Wang Keyi , Nakashoji Ayako , Isozaki Hideko , Hata Aaron , Kufe Donald
Published: December 2023

Background: Osimertinib is an irreversible EGFR tyrosine kinase inhibitor approved for the first-line treatment of patients with metastatic NSCLC harboring EGFR exon 19 deletions or L858R mutations. Patients treated with osimertinib invariably develop acquired resistance by mechanisms involving additional EGFR mutations, MET amplification and other pathways. There is no known involvement of the oncogenic MUC1-C protein in acquired osimertinib resistance.

Methods: H1975/EGFR(L858R/T790M) and patient-derived NSCLC cells with acquired osimertinib resistance (EMT, MET amplified, C797S mutation, or PCBP2-BRAF fusion) were investigated for MUC1-C dependence in studies of EGFR pathway activation, clonogenicity and self-renewal capacity.

Results: We demonstrate that MUC1-C is upregulated in H1975 osimertinib drug tolerant persister (DTP) cells and is necessary for activation of the EGFR pathway. H1975 cells selected for stable osimertinib resistance (H1975-OR) and MGH700-2D cells isolated from a patient with acquired osimertinib resistance are shown to be dependent on MUC1-C for induction of (i) p-EGFR, p-ERK and p-AKT, (ii) EMT, and (iii) the resistant phenotype. We report that MUC1-C is also required for p-EGFR, p-ERK and p-AKT activation and self-renewal capacity in acquired osimertinib-resistant (i) MET amplified MGH170-1D #2 cells, (ii) MGH121 Res#2/EGFR(T790M/C797S) cells, and (iii) MGH845-1R5/EGFR(19del)/PCBP2-BRAF fusion cells. Importantly, targeting MUC1-C in these diverse models reverses osimertinib resistance. To extend these results, we established MET amplified MGH170-1D #2 tumors in mice and found that treatment with GO-203 inhibitor, which is a cell-penetrating peptide that blocks MUC1-C homodimerization, nuclear localization, and function, results in more pronounced inhibition and that the GO-203+osimertinib combination is more effective than either agent alone. In support of these results, high MUC1 expression is associated with poor prognosis for patients with EGFR mutant NSCLCs and those treated with osimertinib.

Conclusions: Our findings demonstrate that MUC1-C is a common effector of osimertinib resistance and is a potential target for the treatment of osimertinib resistant NSCLCs.

Citation Format: Naoki Haratake, Hiroki Ozawa, Yoshihiro Morimoto, Nami Yamashita, Tatsuaki Daimon, Atrayee Bhattacharya, Keyi Wang, Ayako Nakashoji, Hideko Isozaki, Aaron Hata, Donald Kufe. MUC1-C is a common driver of acquired osimertinb resistance in NSCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B089.
Abstract B142: Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers
Authors: Moon Sungho , Cho Seon Yeon , Kim Minhye , Beak Soojeong , Kim Jinhyuk , Kim Yongchan , Park Sungil , Kim Jung-In , Kim Hanseong , Lee In Sang , No Kyoung Tai
Published: December 2023

Hippo pathway plays a critical role in cell apoptosis, proliferation, tissue homeostasis. Dysregulation of Hippo pathway was reported to related to overall aspects of tumorigenesis. The higher expression a YAP/TAZ and TEADs or mutation of core components of hippo pathway, such as  NF2, MST1/2 and LATS1/2  were reported in various cancer subtypes including mesothelioma, meningioma, glioblastoma, non-small cell lung cancer. TEAD auto-palmitoylation is required for protein stability and its transcriptional activity. Inhibiting TEAD activity regulation present attractive strategy for therapeutic intervention in the Hippo pathway. There are increasing proof that the inhibitor to central pocket of TEAD can be promising candidate for cancer treatment. We validated and optimized the hits, derived from our in silico screening system. Our lead compounds inhibiting palmitoylation of TEADs are the potent in vitro activities in TEAD reporter assay and hippo pathway-dysregulated mesotheliomas. In addition, these compounds reduced the expression of TEAD target genes. Furthermore, our compounds strongly inhibited tumor growth in NF2 deficient mouse xenograft model without any adverse events. In these models, our compounds showed excellent PK-PD correlation. Using these compounds, we also tested the possibility as therapy for combination drugs with KRAS inhibitor, EGFR inhibitors. In summary, we have potent TEAD inhibitor series, that showed inhibitory activities of tumor growth in NF2 deficient in vivo models, and may have therapeutic potential in diverse solid tumors.

Citation Format: Sungho Moon, Seon Yeon Cho, Minhye Kim, Soojeong Beak, Jinhyuk Kim, Yongchan Kim, Sungil Park, Jung-In Kim, Hanseong Kim, In Sang Lee, Kyoung Tai No. Discovery of novel and potent TEAD inhibitors, orally available small molecules with anti-tumor activity in hippo pathway- dysregulated cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B142.
Abstract C094: Blocking flotillin-1 palmitoylation abrogates TNBC tumor growth and metastasis
Authors: McClellan Bryan , Graffenried Linda de
Published: December 2023

Flotillin-1 contributes to invasion and metastasis in triple negative breast cancer (TNBC).  Palmitoylation, the process of conjugating palmitoyl-CoA to proteins, plays an essential role in protein stability and trafficking.  Flotillin-1 is modified through palmitoylation, however, the role of its palmitoylation in the context of metastasis has not been explored. Using palmitoylation defective flotillin-1 constructs and loss of function experiments, we have demonstrated that flotillin-1 palmitoylation contributes to its protein stability and metastatic capabilities in vivo. To assess the ability to target flotillin-1 palmitoylation therapeutically, we designed a competitive peptide, which displayed efficacy in blocking flotillin-1 palmitoylation in vitro without altering palmitoylation of other zDHHC5 substrates, highlighting its specificity. Additionally, multiple TNBC tumor models displayed attenuated lung metastasis when expressing a doxycycline inducible flotillin-1 palmitoylation inhibiting peptide construct. The current study has demonstrated the palmitoylation of flotillin-1, a known metastasis inducing protein, to be essential for its protein stability. The demonstrated methods in blocking its palmitoylation through the delivery of a competitive peptide provide proof-of-concept data for further development as a potential targeted therapeutic in TNBC.

Citation Format: Bryan McClellan, Linda de Graffenried. Blocking flotillin-1 palmitoylation abrogates TNBC tumor growth and metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C094.
Abstract C130: Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor
Authors: Pan Weiling , Wang Hui , Qi Fangfei , Deng Haibing , Yang Fei , Yu Hongping , Xu Yao-Chang , Chen Zhui , Ying Haiyan
Published: December 2023

Introduction: MTAP is homozygous deleted in ~50% in glioblastoma and many other cancers. PRMT5*MTA inhibition has been shown to be synthetic lethal with MTAP deletion. First generation PRMT5 inhibitors could not distinguish between PRMT5*MTA or PRMT5 alone, thus limited by their shallow therapeutic windows in clinical use. Development of selective PRMT5*MTA inhibitors may improve not only safety but also therapeutic efficacy. Leveraging advanced computation-aided structural analysis and medicinal chemistry design, we have discovered a potent and selective MTA-cooperative and brain-penetrable PRMT5 inhibitor ABK-PRMT5-1, which demonstrates strong anti-tumor activity and brain-penetrating activity in various preclinical models.

Method: Isogenic cell line pairs (MTAP-/- and MTAP+/+) were used to determine the effects of ABSK-PRMT5-1 on cell proliferation and PRMT5-dependednt downstream signaling. Cancer cell line panel was also used to confirm its activity and selectivity. Its in vivo efficacy was evaluated in cell line derived xenograft (CDX) mouse models with tumors harboring MTAP gene deletion.

Results: ABSK-PRMT5-1 strongly inhibits cell proliferation in MTAP-deleted cancer cell lines, with minimal effects on MTAP wildtype cell lines. Furthermore, it significantly reduces SDMA in MTAP-deleted cancer cell lines. Oral administration of ABSK-PRMT5-1 strongly inhibits tumor growth in MTAP-deleted xenograft tumor models. In addition, ABSK-PRMT5-1 demonstrates strong brain penetration with excellent Kp values in animals. DMPK and safety profiling shows good overall drug-like properties of ABK-PRMT5-1.

Conclusion: ABK-PRMT5-1, presented here by Abbisko Therapeutics, is a highly selective MTA-cooperative and brain-penetrable PRMT5 inhibitor. Its superior profile supports fast-track preclinical development.

Citation Format: Weiling Pan, Hui Wang, Fangfei Qi, Haibing Deng, Fei Yang, Hongping Yu, Yao-Chang Xu, Zhui Chen, Haiyan Ying. Discovery and characterization of an MTA-cooperative and brain-penetrant PRMT5 inhibitor [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C130.
Abstract IA003: Refining our understanding of ADCs: Drug development insights from 40 years of data
Authors: Colombo Raffaele
Published: December 2023

Antibody drug conjugates (ADCs) have emerged as an effective and promising class of cancer therapeutics. Over the past 40 years, over 300 new ADCs have entered the clinic, culminating in 11 FDA approvals to date. Recently, the increased volume of clinical data related to ADCs has substantially advanced our understanding of this therapeutic class. Despite their rising popularity, there are three prevailing ADC dogma that are widely accepted without challenge: - ADCs widen the therapeutic window of the conjugated drug by both increasing the maximum tolerated dose (MTD) and reducing the minimum efficacious dose (MED) of the drug (the therapeutic window dogma). - A highly stable linker is paramount to the clinical success of the ADC (the stability dogma). - ADCs deliver conjugated drugs selectively to cancer cells while sparing normal cells (the magic bullet dogma).   Clinical evidence does not consistently support these beliefs. An improved understanding of how ADCs work is critical to the enhanced design and development of this therapeutic class. Consequently, the canonical ADC dogma need to be refined in light of emerging clinical data. Revised therapeutic window dogma: ADCs do not significantly increase the MTD of their conjugated drugs. Instead, when dosed at or near their MTDs, ADCs exhibit higher efficacy compared to corresponding small molecules. Revised stability dogma: antibody-linker instabilities and linker-drug instabilities are common across many ADCs, including all the approved ADCs (i.e., none of the approved ADCs feature a stable linker). Unexpected toxicities have often emerged among ADCs containing overly stabilized linkers. Revised magic bullet dogma: ADCs significantly alter the exposure of the conjugated drug. Targeted drug delivery and non-targeted uptake, in combination with linker instabilities, contribute to the sustained drug concentration at the tumor site.

Citation Format: Raffaele Colombo. Refining our understanding of ADCs: Drug development insights from 40 years of data [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA003.
Abstract IA015: Leveraging mRNA to design a next-generation cell-based therapeutic cancer vaccine
Authors: Breckpot Karine
Published: December 2023

Monocyte-derived dendritic cell (DC)-based cancer vaccines were shown to activate T cell-mediated antitumor immune responses. To ensure high tumor specificity and potency of the DC-vaccine, we leveraged mRNA for the delivery of tumor antigens and proteins that enhance the DCs’ T-cell stimulatory capacity. With regard to tumor antigens, we studied neoantigens. These originate from erroneous DNA in tumor cells, creating a message for novel and unique tumor antigens of which neoepitopes could be presented by the tumor cells to T cells. Identifying neoepitopes has become possible through advances in next-generation sequencing and bioinformatic prediction algorithms. We developed a synthetic DNA template (SDT) to manufacture in vitro transcribed neoepitope mRNA. A benefit of this platform is the high flexibility and speed to create a neoepitope mRNA library. We showed that mRNA produced with the SDT could be used to validate bioinformatically predicted neoepitopes and could potentially be used to produce a DC-vaccine. With regard to potency, we developed a novel mRNA-based adjuvant, building on the knowledge that interleukin-12 produced by DCs correlates with T-cell activation. The novel mRNA mix, referred to as TetraMix, consists of 4 mRNA molecules encoding (1) constitutively active toll-like receptor 4, (2) CD40 ligand, (3) interferon-gamma and (4) a decoy receptor for interleukin-10. DCs electroporated with TetraMix mRNA showed a viral response gene expression profile. The obtained DC-maturation state enabled activation of tumor killing T cells. In summary, we developed a personalized cancer vaccine consisting of mRNA-engineered DCs, which is ready for evaluation in a clinical setting.

Citation Format: Karine Breckpot. Leveraging mRNA to design a next-generation cell-based therapeutic cancer vaccine [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr IA015.
Abstract LB_A05: Coadministration of AZD 4573 and gilteritinib exhibits a potent activity in FLT3 inhibitor-sensitive and -resistant AML cells
Authors: Rahmani Mohamed , Salah Baraa Khalid , Yener Burcu , Mahboub Bassam , Grant Steven
Published: December 2023

Acute myeloid leukemia (AML) is caused by the sequential acquisition of mutations that regulate multiple cellular pathways, indicating that multiple pathways must be coordinately inhibited for a successful therapy in this disease. Transcriptomics analysis suggest that exposure of AML cells to the selective CDK9 inhibitor AZD4573 led to activation of multiple survival pathways including MAPK, PI3K, and STAT suggesting that disruption of these signaling pathways may potentiate this agent activity. Notably, combined treatment with AZD4573 and the FLT3 inhibitor gilteritinib resulted in a robust suppression of cell growth and a marked induction of apoptosis in various AML cell lines, particularly those with FLT3 mutations. These were associated with a marked induction of apoptosis reflected by increased Annexin V/PI positivity and cleavage in caspase 3 and its substrate PARP. Importantly, combined treatment was also highly effective in FLT3 mutants AML cells that exhibit significant resistance to various FLT3 inhibitors including gilteritinib. Combined treatment led to a profound disruption of critical survival signaling pathways including MEK/ERK, STAT, and PI3K/AKT pathways. Combined treatment also significantly disrupted the balance between the proapoptotic and anti-apoptotic Bcl-2 members as reflected by downregulation of MCL1 and upregulated of Bim protein levels. Importantly, GILT/AZD4573-induced cell death was fully prevented when Bax and Bak were knocked out using CRISPR system, suggesting that the anti-AML activity of this regimen proceeds mainly via the mitochondrial apoptotic pathway. Finally, using a systemic acute myeloid leukemia xenograft model, co-administration of gilteritinib and AZD4573 sharply reduced leukemia growth and markedly prolonged mice survival. Collectively, these findings demonstrate that dual inhibition of CDK9 and FLT3 exhibits a potent anti-leukemic efficacy in vitro and in vivo. These findings also indicate that this strategy warrants further attention in FLT3-dependent acute myeloid leukemias.

Citation Format: Mohamed Rahmani, Baraa Khalid Salah, Burcu Yener, Bassam Mahboub, Steven Grant. Coadministration of AZD 4573 and gilteritinib exhibits a potent activity in FLT3 inhibitor-sensitive and -resistant AML cells [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A05.
Abstract LB_A19: Genome-wide CRISPR/Cas9 screens for the identification of targeted vulnerabilties in PARP inhibitor-resistant PARG;BRCA2-deficient tumor cells: A focus on EXO1/FEN1-mediated DNA repair
Authors: Andronikou Christina , Burdova Kamila , Dibitetto Diego , Lieftink Cor , Beijersbergen Roderick L. , Hanzlikova Hana , Jonkers Jos , Rottenberg Sven
Published: December 2023

Targeting poly(ADP-ribose) glycohydrolase (PARG) is currently explored as a therapeutic approach to treat various cancer types, but we have a poor understanding of the specific genetic vulnerabilities that would make cancer cells susceptible to such a tailored therapy. Moreover, the identification of such vulnerabilities is of interest to target BRCA2;p53-deficient tumors that have acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi), through loss of PARG expression. Here, by performing whole genome CRISPR/Cas9 drop-out screens we identify various genes involved in DNA repair to be essential for the survival of PARG;BRCA2;p53-deficient cells. In particular, our findings reveal EXO1 and FEN1 as major synthetic lethal interactors to PARG loss. We provide evidence that PARG;BRCA2;p53-deficient cells exhibit compromised replication fork progression, DNA single-strand break repair and Okazaki fragment processing, alterations that exacerbate and become lethal upon EXO1/FEN1 inhibition. Since this sensitivity is dependent on BRCA2 defects, we propose EXO1/FEN1 targeting in PARPi-resistant tumors that have lost PARG activity. Moreover, EXO1/FEN1 targeting may be a useful strategy to enhance the effect of PARG inhibitors in HR-deficient tumors.

Citation Format: Christina Andronikou, Kamila Burdova, Diego Dibitetto, Cor Lieftink, Roderick L. Beijersbergen, Hana Hanzlikova, Jos Jonkers, Sven Rottenberg. Genome-wide CRISPR/Cas9 screens for the identification of targeted vulnerabilties in PARP inhibitor-resistant PARG;BRCA2-deficient tumor cells: A focus on EXO1/FEN1-mediated DNA repair [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A19.
Abstract LB_B18: Rapid and reproducible scaffold free organoid formation for personalized medicine: Multiomic analysis of in-vitro cancer patient model
Authors: Chang Ying-Chih
Published: December 2023

We have established a single cell derived 3D organoid culture platform, Rapid, Reproducible, Rare Cell 3D Expansion (R3CE), and demonstrated its ability to generate 3D organoids of solid tumors, normal tissues from surgical tissues and needle biopsies in one week. The successful banking of at least two passages with over 10^6 cells is over 90% (breast cancer ( n=7, stages I to IV), colorectal cancer (n = 9 stages I to III), hepatoma cancer (n = 2, stage IV), and ovarian cancer (n =2, stage IV)). The quick formation of patient derived organoids have been consistently passed over 20 passages, and their H&E staining, WES, and protein markers have shown their high fidelity from the original tissues and passages over 11th generation. The normal and tumor organoid pairs were recently tested for direct cytotoxic events by co-culturing with various immunotherapy, including CAR-T and autologous NK testing. This is the first 3D organoid system that does not require aggregation, or 3D scaffold such as matrigel system. Hence, it opens up the possibility for drug assays, from small molecules, large molecules to cell regiments.

Citation Format: Ying-Chih Chang. Rapid and reproducible scaffold free organoid formation for personalized medicine: Multiomic analysis of in-vitro cancer patient model [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B18.
Abstract A067: Perceptions and experiences of Black women on hereditary breast and ovarian cancer genetic testing
Authors: Riggan Kirsten A. , Halyard Michele , James Sarah E. , Kelly Marion , Phillips Daphne , Allyse Megan A.
Published: December 2023

Black women experience significant disparities in morbidity and mortality related to hereditary breast and ovarian cancer (HBOC). Early identification of women with HBOC is essential for proactive screening and timely diagnosis but evidence suggests that Black women receive genetic testing for HBOC at lower rates than their White counterparts. To understand Black women’s perspectives on HBOC genetic testing and potential factors influencing this decision, we conducted in-depth qualitative interviews with 107 Black women with a personal or family history of breast or ovarian cancer. Participants were recruited via the networks of patient support organizations and sororities as well as at a family medicine safety net clinic in Jacksonville, FL. Participants frequently expressed a lack of awareness about their family cancer history; many cancer patients stated that they only became aware of extensive family history upon their own diagnosis. Lack of family history sharing was attributed to a culture of silence around medical issues and a desire to protect family members from difficult information. However, most participants indicated a strong desire to understand their own risk of HBOC and were interested in genetic testing. Participants with a personal diagnosis were motivated to undergo HBOC genetic testing to reduce the risk for future generations. Clinical experiences with the offer of HBOC genetic testing were variable, with a few expressing that they had to make repeated inquiries from a provider to understand the relevance of the test to their own health. These findings suggest that investigation into alternative clinical modalities to collect family health history may be beneficial to identify Black women who meet NCCN Guidelines for HBOC testing. In contrast to the literature suggesting hesitancy for HBOC genetic testing, many participants  perceived genetic results as having a positive impact for their medical decision-making and family's health. The development of patient materials and provider education on cultural and social factors that influence the uptake of HBOC genetic testing is also needed. 

Citation Format: Kirsten A. Riggan, Michele Halyard, Sarah E. James, Marion Kelly, Daphne Phillips, Megan A. Allyse. Perceptions and experiences of Black women on hereditary breast and ovarian cancer genetic testing [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr A067.
Abstract B113: A multi-ethnic population-based study of multiple myeloma disparities: Results from a recruitment pilot
Authors: Vang April P. , Perez Angelica , Quino Juanita Elizabeth , Estrada Ana , Stewart Eric , Cress Rosemary , Carvajal-Carmona Luis
Published: December 2023

To understand multiple myeloma (MM) incidence and survivorship disparities, we established the Precision MEDicine, EqUity and Disparities Research in MultipLe MyeLomA (MEDULLA) study. Our study contacted 400 MM patients reported to the Cancer Registry of Greater California (CRGC) between 2013-2018. We contacted 100 adult individuals from four racial/ethnic groups: Blacks, Whites, Latinos, and Asians with MM diagnosis. Data collection included variables reported to the CRGC, a self-administered survey, and biospecimen saliva collection. The survey focused on demographics, risk factors, cancer treatment, family history, quality of life, and social determinants of health. We also used census tract level features obtained by the American Community Survey 2007-2011. A total of 95 patients participated in the survey (overall response rate = 24%). We performed chi-square test, fisher’s exact test, or Wilcoxon test to obtain two-sided p-values for univariate testing for associations with responding to the survey. We further perform multivariable logistic regression using a stepwise approach under the Akaike information criterion with age and sex kept as covariates. These methods were stratified by Whites and Non-Whites separately which we were able to find important trends.  The highest response received was from Whites at 44.2%, with significantly lower rates in all minority groups (<20% for all groups). Response rates were higher for patients living in areas with higher median annual incomes and education. For every 1% increase in poverty rates, Whites living in such neighborhoods were 3% less likely to respond to the survey (p=0.04). For every 10% increase in the proportion of individuals having a college degree, responding to the survey increased by 1.17 units for minorities in that neighborhood (p=0.07). Minorities living in neighborhoods with high proportions of adults without a high school diploma and high unemployment rates are less likely to respond (p=0.02 and p=0.047, respectively). In conclusion, we found significantly lower participation rates among minority groups, with socio-economic factors affecting response rates. We suggest that future studies develop community-focused and culturally tailored strategies to understand MM etiology and survivorship in such populations.

Citation Format: April P. Vang, Angelica Perez, Juanita Elizabeth Quino, Ana Estrada, Eric Stewart, Rosemary Cress, Luis Carvajal-Carmona. A multi-ethnic population-based study of multiple myeloma disparities: Results from a recruitment pilot [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr B113.
Abstract IA035: Narrowing disparities in breast cancer: A multi-level perspective
Authors: McCullough Lauren E.
Published: December 2023

Seminar Abstract: Despite improvements in breast cancer detection and treatment, racial disparities in breast cancer outcomes persist. In the United States, particularly the southeastern region, Black women are more likely to experience breast cancer-related mortality than any other race or ethnic group—regardless of subtype, age, or socioeconomic status. The drivers of disparities are likely multifactoral and include interacting factors (e.g., tumor, treatment, patient, and neighborhood characteristics) that contribute to race differences in breast cancer-specific mortality. Emerging data suggest that the excess breast cancer mortality experienced by Black women is linked to broader systems of oppression that impact everything from access and quality of care to tumor aggressiveness and treatment response—the imprints of which may be detectable in tumor biology. Comprehensive, multi-level approaches to addressing disparities will aid the identification of causal and contributing factors, moving us beyond merely documenting differences to creating action-oriented models aimed at achieving equitable cancer care within the social contexts of the communities affected.

Citation Format: Lauren E. McCullough. Narrowing disparities in breast cancer: A multi-level perspective [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr IA035.
Cancer Prevention Perspective: The University of Kansas Cancer Center
Authors: Jensen Roy A. , Befort Christie A.
Published: December 2023

Despite the incredible progress that has been made against cancer over the last few decades, the demographic trends in the United States predict that we will see significant increases in cancer incidence and mortality by the year 2030. This, coupled with an aging cancer workforce, would suggest that we will have major challenges ahead in dealing with the increasing burden from cancer. Clearly a critical part of our strategy must be to focus on cancer prevention and control (CPC) efforts and not solely rely on treatment to mitigate this concerning trend. This review discusses how the University of Kansas Cancer Center has had a longstanding emphasis on CPC and has leveraged this expertise to enhance the effectiveness and impact of our community outreach and engagement efforts.