tbuckley/cabot-search huggingface dataset:
Abstract IA26: Exploring breast cancer vulnerabilities through apoptotic pathways
Authors: James R Whittle, François Vaillant, Elliot Surgenor, Luuk Heitink, Christine Muttiah, Jane E Visvader, Geoffrey J Lindeman
Journal: Cancer Research (2024)

Abstract Combined CDK4/6 inhibitor and endocrine therapy has rapidly become standard therapy for patients with early line relapsed estrogen receptor (ER)-positive, HER2-negative breast cancer. Although this combination has been shown to significantly improve progression free and overall survival, relapse is virtually inevitable. This may in part be due to the profound cytostatic effect of CDK4/6 inhibitors on tumors, which is associated with reduced apoptotic cell death. It seems likely that growth arrested and/or senescent tumor cells acquire resistance to therapy, leading to relapse. BH3 mimetics are an emerging class of drug that target pro-survival proteins such as BCL2, BCL-xL and MCL1. Venetoclax, a BH3 mimetic that has potent and specific activity against BCL2, has shown considerable promise in hematopoietic tumors such as CLL, but has yet to be fully explored in solid tumors. We have previously demonstrated safety and efficacy of combining tamoxifen with venetoclax for patients with metastatic ER-positive BCL2-positive disease using pre-clinical PDX models and a dose-finding phase 1 study [mBEP study, ISRCTN98335443], where most patients were CDK4/6 inhibitor therapy-naïve. In the post-CDK4/6 inhibitor setting, however, venetoclax did not improve clinical benefit rate or progression free survival when added to fulvestrant in the phase 2 study VERONICA [NCT03584009]. In that study a minority of tumours exhibited strong BCL2 expression and exploratory biomarker analysis revealed a trend towards improved progression free survival for patients with tumors exhibiting high BCL2 expression (IHC 3+), a BCL2:BCL-xL Histoscore ratio ≥1, or with PIK3CA wild-type status. Using pre-clinical models including patient derived xenografts of ER-positive breast cancer, we have shown that the addition of venetoclax to dual therapy comprising fulvestrant and the CDK4/6 inhibitor palbociclib elicits a superior and more durable tumor response, accompanied by increased apoptosis. These findings have formed the basis of a phase 1 clinical trial of palbociclib, letrozole and venetoclax [PALVEN, NCT03900884] in patients with early line relapsed ER and BCL2-positive metastatic breast cancer. In parallel, pre-clinical studies are underway to determine the effect of dual targeting BCL-xL and MCL1, as well as dual targeting of AKT and with a BH3 mimetic in CDK4/6 inhibitor refractory breast cancer cells. Citation Format: James R Whittle, François Vaillant, Elliot Surgenor, Luuk Heitink, Christine Muttiah, Jane E Visvader, Geoffrey J Lindeman. Exploring breast cancer vulnerabilities through apoptotic pathways [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA26.
Efficacy and safety of daratumumab with ixazomib and dexamethasone in lenalidomide‐exposed patients after one prior line of therapy: Final results of the phase 2 study <scp>DARIA</scp>
Authors: Evangelos Terpos, Ioannis Ntanasis‐Stathopoulos, Maria Gavriatopoulou, Eirini Katodritou, Evdoxia Hatjiharissi, Panagiotis Malandrakis, Evgenia Verrou, Stavros Golfinopoulos, Magdalini Migkou, Kyriaki Manousou, Sosana Delimpasi, Argiris Symeonidis, Efstathios Kastritis, Meletios A. Dimopoulos
Journal: American Journal of Hematology (2024)

Abstract The use of lenalidomide in frontline therapy for patients with newly diagnosed multiple myeloma (MM) has increased the number of those who become refractory to lenalidomide at second line. In this context, we assessed the efficacy of daratumumab in combination with ixazomib and dexamethasone (Dara‐Ixa‐dex) in the prospective phase 2 study DARIA. Eligible patients had relapsed/refractory MM (RRMM) after one prior line with a lenalidomide‐based regimen. The primary endpoint was overall response rate (ORR). Secondary endpoints included survival outcomes, safety and changes in biomarkers of bone metabolism. Overall, 50 patients were enrolled (median age 69 years, 56% males). 32 (64%) patients were refractory to lenalidomide, and 17 (34%) had undergone autologous transplant. The ORR was 64% ( n = 32); whereas 17 (34%) had a very good partial response or better. The median time to first response was 1.0 month. After a median follow‐up of 23.4 months, the median PFS and OS were 8.1 and 39.2 months, respectively. Furthermore, significant changes in markers of bone metabolism became evident as early as at 6 months on treatment. Regarding safety, 21 (42%) patients had ≥1 grade 3/4 adverse event (AE); the most common was thrombocytopenia ( n = 9, 18%). 14 (28%) patients had ≥1 serious AE (SAE), the most common being acute kidney injury and pneumonia ( n = 2, each). Four patients died due to infections. In conclusion, second‐line treatment with Dara‐Ixa‐dex in patients with RRMM pre‐treated with a lenalidomide‐based regimen resulted in rapid responses along with a favorable effect on bone metabolism.
Abstract A051: Mitochondrial metabolism and fission as dynamic drivers of breast cancer metastasis
Authors: Hannah Savage, Dennis Ma, Devon Lawson
Journal: Cancer Research (2024)

Abstract Approximately 30% of women with early-stage breast cancer will develop metastatic disease, making efforts to define drivers of metastasis critical. Our group found that metastatic breast cancer cells express an oxidative phosphorylation (OXPHOS) gene signature. Further, inhibiting OXPHOS reduced metastatic seeding, thus revealing the functional role of mitochondrial metabolism in breast cancer metastasis. It is understood that mitochondria are highly dynamic organelles that are regulated by a balance of fission and fusion proteins; however, it remains poorly understood how mitochondrial metabolism and their dynamics promote cancer spreading. To interrogate mitochondrial heterogeneity within primary tumors, we sorted tumor cells from patient derived xenograft (HCI010) and murine (4T1) breast tumors stratified by low or high uptake of tetramethylrhodamine methyl ester (TMRM, a dye that accumulates in active mitochondria undergoing OXPHOS). Low or high cell fractions were re-injected intravenously in new cohorts of mice. We found greater metastatic burden in the lungs of mice injected with the TMRM high fraction. Furthermore, we uncovered that the TMRM high cells had greater mitochondria abundance than TMRM low cells. We hypothesized the differences in mitochondrial content we observed in primary tumor cells is caused by shifts in cellular expression of mitochondria fission and fusion proteins. Consistent with this hypothesis, we found that TMRM high, metastatic tumor cells had greater expression of mitochondria fission gene, DRP1, and lower expression of fusion gene, MFN2. Collectively, our results revealed heterogeneity in tumor cell mitochondrial content within a primary tumor that appears to influence the fitness of a cell to metastasize. Lastly, our data supports a role for mitochondrial fission in breast cancer metastasis. Future directions for our studies will include genetic and pharmacological modulation of mitochondrial fission and fusion to better understand why it influences metastasis and at what point during the metastatic cascade. Citation Format: Hannah Savage, Dennis Ma, Devon Lawson. Mitochondrial metabolism and fission as dynamic drivers of breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A051.
Abstract A044: P2Y2 signaling disruption reduces ATP-dependent calcium elevation and actin localization to promote breast tumor cell dissemination
Authors: Makenzy Mull, Stephen Pratt, Keyata Thompson, David Annis, Julia Ju, Megan Stemberger, Liron Boyman, Michele Vitolo, W. Jonathan Lederer, Stuart Martin
Journal: Cancer Research (2024)

Abstract The tumor microenvironment and wound healing after injury both contain extremely high concentrations of the extracellular signaling molecule, adenosine triphosphate (ATP) compared to normal tissue. P2Y2 receptor, an ATP-activated purinergic receptor, is typically associated with pulmonary, endothelial, and neural cell signaling. Here we report the importance of ATP-dependent P2Y2 signaling in breast epithelial cells and how it is altered in metastatic breast cancer. In response to ATP activation, P2Y2 receptor signaling causes an increase of intracellular calcium (Ca2+) in non-tumorigenic breast epithelial cells, while their tumorigenic and metastatic counterparts have significantly reduced Ca2+ responses. The non-tumorigenic cells respond to increased Ca2+ with actin polymerization and localization to cell edges, while the metastatic cells remained unaffected. The increase in intracellular Ca2+ after ATP stimulation was blunted using a P2Y2 antagonist, which also prevented actin mobilization and caused cell dissemination from spheroids in non-tumorigenic breast epithelial cells. Furthermore, the lack of Ca2+ concentration changes and actin mobilization in the metastatic breast cancer cells could be due to reduced P2Y2 expression, which correlates with poorer overall survival in breast cancer patients. This study elucidates rapid changes that occur after elevated intracellular Ca2+ in breast epithelial cells and how metastatic cancer cells have adapted to evade this cellular response. Citation Format: Makenzy Mull, Stephen Pratt, Keyata Thompson, David Annis, Julia Ju, Megan Stemberger, Liron Boyman, Michele Vitolo, W. Jonathan Lederer, Stuart Martin. P2Y2 signaling disruption reduces ATP-dependent calcium elevation and actin localization to promote breast tumor cell dissemination [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A044.
Abstract A001: Transcriptomic and microRNA profiling revealed novel therapeutic targets for breast cancer subtypes
Authors: Ramesh Elango, Radhakrishnan Vishnubalaji, Sameera Rashid, Nehad Alajez
Journal: Cancer Research (2024)

Abstract Numerous studies suggested breast cancer (BC) from the Middle East and North Africa (MENA) to be presented at younger age with advanced tumor grade, suggesting underlying biological differences. Given the limited transcriptomic profiling data on BC from the MENA region, we performed mRNA and microRNA (miRNA) transcriptomic profiling on a local cohort of BC (n=96) from Qatar. Our data revealed the differentially expressed genes and miRNAs in relation to BC molecular subtypes (HR+, HER2+, HER2+HR+, and TNBC), tumor grade (high vs low), patients’ age (young (≤ 40) vs old (&amp;gt; 40)), and ethnicity (MENA vs non-MENA). Our data revealed close similarity between TNBC and HER2+, while the transcriptome of HER2+HR+ tumor was similar to that from HR+ tumors. Integrated network analysis identified complex miRNA-mRNA regulatory networks in each BC molecular subtype, in high vs low grade tumors, in tumors from young vs old, and in tumors from MENA vs non-MENA, thus implicating miRNA-mediated gene regulation as an key mechanism in shaping the transcriptome of BC. Integration of our transcriptomic data with CRISPR-Cas9 functional screen data and the Drug-Gene Interaction Database identified numerous dependencies and therapeutic vulnerabilities for each BC molecular subtype. Among those, CDC123 was functionally validated as potential therapeutic target for TNBC. Survival analyses identified mRNA and miRNA-based signatures predicative of relapse free survival (RFS), which were validated in larger BC cohorts. Our data provides comprehensive transcriptomic profiling and unraveled the miRNA-mRNA regulatory networks in BC patients from the region and identified numerous actionable gene targets, employing integrated approach. Findings from the current study have potential implications to improve the current standard-of-care for BC from the MENA as well as patients from other ethnicities. Citation Format: Ramesh Elango, Radhakrishnan Vishnubalaji, Sameera Rashid, Nehad Alajez. Transcriptomic and microRNA profiling revealed novel therapeutic targets for breast cancer subtypes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A001.
Abstract A012: Molecular profiling of neoductgenesis in early stage breast cancer for the development of novel diagnostic biomarkers
Authors: Laura Lehtinen, Leena Koskinen, Markus Peurla, Emilia Huotari, Otto Kauko, Peter Dean, Pauliina Hartiala, Pia Boström, Emilia Peuhu
Journal: Cancer Research (2024)

Abstract Ductal carcinoma in situ (DCIS) is the most common precancerous finding in mammography screens. DCIS generally has a good prognosis, and only 20-25% of the cases progress to invasive breast carcinoma (IBC) even if left untreated. Breast pathologists and radiologists have suggested that there are currently more than one kind of DCIS under the same diagnosis. A subset of DCIS cases with reduced survival rate are associated with casting-type calcifications that can be histologically detected within closely packed, contorted, newly formed ducts, a phenomenon called neoductgenesis. Tumors with neoductgenesis are often erroneously diagnosed as DCIS, while in fact, they are associated with higher degree of metastasis and should be considered invasive carcinomas. This tumor category currently lacks specific histopathological markers and the biological processes leading to metastasis via neoductgenesis remain poorly characterised. To reveal new information of this breast tumor type, we are currently conducting comprehensive characterization of FFPE tissue samples of DCIS cases with and without neoductgenesis using imaging mass cytometry analysis and immunohistochemistry of specific tumor areas. Preliminary results on immunofluorescence staining suggest that neoductgenesis is associated with changes in the expression of specific myoepithelial marker proteins compared to areas with pure DCIS. In addition, we are analysing the three-dimensional ductal architecture of these lesions. The information obtained from this study can lead to development of new diagnostic tools for the identification of early breast cancers with a higher risk of spreading. Early detection of these cases is important to ensure the effectiveness and timeliness of treatment, and at the same time to improve the patients' quality of life. Citation Format: Laura Lehtinen, Leena Koskinen, Markus Peurla, Emilia Huotari, Otto Kauko, Peter Dean, Pauliina Hartiala, Pia Boström, Emilia Peuhu. Molecular profiling of neoductgenesis in early stage breast cancer for the development of novel diagnostic biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A012.
Abstract IA13: Molecular and genomic mechanisms of estrogen signaling and gene regulation in breast cancer
Authors: W. Lee Kraus
Journal: Cancer Research (2024)

Abstract Transcriptional enhancers function as nucleation sites for the assembly of transcription-regulating complexes across the genome, which act to drive cell type-specific patterns of gene expression. Although many features of active enhancers [e.g., H3K4me1, H3K27ac, enrichment of p300/CBP and Mediator, and production of enhancer RNAs (eRNAs)] have been defined by genomic assays, the roles of these features in estrogen receptor alpha (ERa) enhancer function are not well understood. We are interested in how the molecular underpinnings of ERa enhancer formation and activity control the gene expression programs that drive breast cancer phenotypes and responses to therapeutic agents. We have used a variety of molecular, biochemical, genomic, genetic, and computational approaches to determine the following aspects of ERa enhancers biology in hormone-responsive breast cancer cells: (1) where ERa enhancers are formed across the genome, (2) the kinetics of ERa enhancer formation and disassembly, (3) the influence of genetic variation on ERa enhancer function, (4) the role of the enhancer features noted above in ERa enhancer function, and (5) how protein complexes and small polypeptides serve as coregulators to drive ERa transcriptional activity. Our current focus has been on eRNAs, which are poorly characterized noncoding RNAs that are thought to regulate enhancer function and gene expression. We have identified a ~40 nucleotide functional eRNA regulatory motif (FERM) present in many estrogen-regulated eRNAs that promotes gene expression by increasing ERα recruitment and stimulating p300-catalyzed H3K27 acetylation. In addition, we have been examining how the dose of estrogen impacts the efficiency of enhancer assembly by ERα. Finally, we have been exploring the role of PARP1, a ubiquitous chromatin-associated regulator, and small polypeptides derived from “non-coding” RNAs, control ERa enhancer function. In all cases, we perform analyses to link enhancer function to gene expression outcomes and breast cancer biology. Collectively, our results demonstrate the biological and mechanistic roles of eRNAs in breast cancer. This work is supported by grants from the NIH/NIDDK (DK058110) and CPRIT (RP160319) to W.L.K. Citation Format: W. Lee Kraus. Molecular and genomic mechanisms of estrogen signaling and gene regulation in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr IA13.
Abstract B070: Myc synthetic lethality as a therapeutic strategy for resistance: Insights into the targetability of mitochondrial complex I in Myc-high TNBC
Authors: Antti O Hiltunen, Linda J Id, Juha Klefström
Journal: Cancer Research (2024)

Abstract Patients with advanced triple-negative breast cancer (TNBC) frequently develop chemoresistance, emphasizing an urgent need for novel therapeutic strategies able to eradicate treatment resistant tumor cells. Recent studies have highlighted MYC as a common oncogenic alteration and a driver of stem-like TNBC phenotype, which commonly features high mitochondrial respiratory activity instated through OXPHOS system and chemoresistance. Interestingly, emerging evidence suggests that residual tumors from chemo treatment remain susceptible to OXPHOS inhibition through inhibition of respiratory complex I. Our previous studies have revealed a specific MYC-dependent and tumor suppressive synthetic lethal action for combination of metformin and BH3 mimetics in cells, ex vivo and in vivo models of aggressive breast cancer (PMID: 30728358). Metformin is a systemic and local metabolic modulator, which acts as a weak complex I inhibitor and promoter of AMPK activation. Here, we have explored the role of MYC in OXPHOS regulation, to address the question if metformin specifically and lethally targets MYC-modulated OXPHOS in MYC-high TNBC. We found that a selective c-MYC inhibitor (EN4) leads to a significant decrease in complex I activity despite only a modest drop in complex I mass in endogenously MYC-high TNBC cell lines. Conversely, engineered MYC overexpression in these cells upregulated complex I activity. Our current work explores transcriptomic, proteomic, and functional approaches to the mechanisms through which MYC regulates complex I activity, structure, and dynamics, ultimately hoping to define a biological rationale for therapeutic targeting of OXPHOS in Myc-high TNBC. Citation Format: Antti O Hiltunen, Linda J Id, Juha Klefström. Myc synthetic lethality as a therapeutic strategy for resistance: Insights into the targetability of mitochondrial complex I in Myc-high TNBC [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B070.
Abstract A023: lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer
Authors: Kacie D Waiters, Maram Quttina, Ashfia F Khan, Samaneh Karami, Anthony Peidl, Funmi Babajide, Tasneem Bawa-Khalfe
Journal: Cancer Research (2024)

Abstract Hormone receptor positive (HR+) breast cancer (BCa) is the most frequently diagnosed BCa type accounting for 70% of all breast cancer cases. A large population of HR+ BCa patients (30-40%) are resistant to mainstay endocrine therapy and develop incurable metastatic disease. Hence, it is imperative to identify viable biomarkers that stratify patients as drug responders or non-responders. Emerging scientific literature highlights the essential role of long non-coding RNAs (lncRNA), a class of RNAs over 200 nucleotides in length that do not encode protein, in cancer drug resistance and metastatic transformation. Major biological functions of lncRNA rely on association with select protein interactors. As lncRNA equally bind proteins with and without canonical RNA-binding motifs, it is unclear what facilitates this lncRNA-protein interaction. Our recent studies show that SUMO post-translational modification (or SUMOylation) of target proteins potentiates binding with lncRNA, particularly at the chromatin. SUMOylation of heterochromatin protein 1 α (HP1α) drives interaction with multiple chromatin-associated lncRNA both within and outside canonical heterochromatin foci. Interaction with lncRNA supports SUMOylated HP1α’s unconventional function as a transcriptional repressor at select euchromatic loci. We now report an inverse relationship in which SUMOylated HP1α directs the stability of its lncRNA binding partner. Specifically, SUMO-modified HP1α directs cell-cycle dependent recruitment of the RNA degradation machinery to the chromatin and facilitates clearance of chromatin-bound lncRNA. This dynamic lncRNA degradation process is disturbed with cancer onset and instead favors aberrant cancer cell transformation. Consistently, restoring lncRNA degradation homeostasis decreases metastatic properties of HR+ BCa cells and increases sensitivity to targeted therapeutics currently in clinical trials. Our studies define a fundamental mechanism that dictates lncRNA stability and/or degradation in BCa cells. In addition, we present viable biomarkers that predict sensitivity to ET and alternative targeted therapies. Citation Format: Kacie D Waiters, Maram Quttina, Ashfia F Khan, Samaneh Karami, Anthony Peidl, Funmi Babajide, Tasneem Bawa-Khalfe. lncRNA-protein interactions that predict response to endocrine therapy in HR+ breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A023.