tbuckley/cabot-search huggingface dataset:
Abstract LB299: Clinical pharmacokinetics and peripheral receptor occupancy of OR502, best-in-class antibody against leukocyte immunoglobulin-like receptor B2 (LILRB2), alone and in combination with cemiplimab
Authors: Andrae Vandross, David Sommerhalder, Mohamad Salkeni, Damien Cronier, Myriam N. Bouchlaka, Kamal Puri, Nenad Sarapa, Lesley Skingley, Mike Yefimenko, Alice Bexon, Shiraj Sen
Journal: Cancer Research (2025)

Abstract Background: Based on its single-agent clinical activity and excellent safety profile, OR502 has best-in-class properties. Preclinically, OR502 reverses and prevents myeloid cell-mediated immune suppression and restores T cell functions with superior activity than other antibodies targeting LILRB2. OR502 binds to a distinct epitope of LILRB2, and blocks more broadly LILRB2 binding to its ligands. In addition, OR502 co-engages activating FcγR on myeloid cells. Here we report pharmacokinetic (PK) and receptor occupancy (RO) data from a phase 1 study [NCT06090266] dose escalation cohorts in patients with refractory solid tumors. Methods: Primary objectives included selection of an OR502 dose for the next stage of study, supported by LILRB2 RO and PK in addition to safety and efficacy. OR502 was given IV in 21-day (D) cycles (C) in 5 cohorts from 100-1600 mg in 2 separate escalations: monotherapy (mono) or + standard dosing of cemiplimab (combo). Serial PK sampling was performed during C1 and C3, then D1 every other C. Peripheral RO was assessed weekly during C1 and C3 and on D1 of C2 and C4 by flow cytometry. An OR502 anti-idiotype was used to measure OR502 bound to LILRB2 on the surface of myeloid cells vs unoccupied and total LILRB2 before and after OR502 administration. PK data were analyzed using PKanalix®. Results: Table summarizes patient characteristics, PK and RO from mono and combo escalation cohorts. Conclusions: OR502 PK and RO support Q3W dosing, and based on near-complete RO and predictable PK, justify the OR502 dose selected for mono and combo expansion cohorts of 800 mg IV Q3W in PD-(L)1 pretreated cutaneous melanoma and NSCLC, respectively. Citation Format: Andrae Vandross, David Sommerhalder, Mohamad Salkeni, Damien Cronier, Myriam N. Bouchlaka, Kamal Puri, Nenad Sarapa, Lesley Skingley, Mike Yefimenko, Alice Bexon, Shiraj Sen. Clinical pharmacokinetics and peripheral receptor occupancy of OR502, best-in-class antibody against leukocyte immunoglobulin-like receptor B2 (LILRB2), alone and in combination with cemiplimab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB299.
Abstract LB293: Distinct regulation of Cyclin D mediates heterogenous response to RAS inhibition in colorectal cancer models
Authors: Philip Choi, Julia Meredith, Mallika Singh, Neal Rosen
Journal: Cancer Research (2025)

Abstract KRAS inhibitors have demonstrated limited efficacy as monotherapy in KRAS-mutant colorectal cancer (CRC). Here we tested a RAS(ON) multi-selective inhibitor (RMC-7977) in KRAS-mutant CRC models in vitro and find a heterogeneous response to treatment. We analyzed variables that correlate with sensitivity and find that the degree of Cyclin D1 inhibition upon RMC-7977 treatment correlates strongly with overall sensitivity to the inhibitor. We find the level of inhibition of Cyclin D1 by RMC-7977 reflects the extent of ERK dependency of its mRNA expression levels. On one end of the spectrum are cell lines in which Cyclin D1 mRNA (CCND1) is strongly ERK-dependent. In these cells, either RMC-7977 or the MEK inhibitor trametinib are sufficient to fully inhibit Cyclin D1 and cause G1 cell cycle arrest. In these tumors, resistance to RAS or MEK inhibition arises through ERK-pathway re-activation and a rebound in CCND1 mRNA. A vertical inhibition strategy with RAS + MEK inhibition to fully and/or durably suppress ERK pathway activation leads to decreased cell proliferation and increased apoptosis in these cells, exemplifying the need for a combinatorial approach to achieve complete RAS pathway inhibition in this context. On the other end of the spectrum are cell lines in which Cyclin D1 mRNA levels are relatively ERK-independent. In these lines, CCND1 mRNA and protein expression persist despite trametinib or RMC-7977 treatment. We observe that these tumor cell lines are often associated with PI3K pathway or HER2 alterations. We find that in these cells, RAS + PI3K combination inhibition can more effectively block cap-dependent Cyclin D1 protein translation through its negative effect on mTORC1 activity. In addition, PI3K inhibition, but not mTOR inhibition, can also further synergize with RAS inhibition by downregulating CCND1 mRNA. Thus, we find a potential mechanism of resistance to RAS inhibition in CRC is persistent Cyclin D1 expression, mediated either through ERK-pathway re-activation or a shift in CCND1 mRNA regulation away from the ERK pathway. Depending on the tumor’s distinct regulation of Cyclin D1, its full suppression can be achieved through increased inhibition of RAS-MAPK pathway signaling or a parallel inhibition strategy with RAS + PI3K combination inhibition. Citation Format: Philip Choi, Julia Meredith, Mallika Singh, Neal Rosen. Distinct regulation of Cyclin D mediates heterogenous response to RAS inhibition in colorectal cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB293.
Abstract LB342: Learning contextual determinants of cytokine signaling during immunity
Authors: Samuel A. Rose, Russell Kunes, Thomas Walle, Suhani Balachandran, Roshan Sharma, Dana Pe'er
Journal: Cancer Research (2025)

Abstract Cytokine action depends on the context of the receiving cell—its type, location, and cytokine milieu. Previous work has mapped the transcriptional response to cytokine treatments across experimental contexts. However, current reference sets do not reflect the full cell-type continuum; they are frequently derived from non-physiological contexts; and they are treated as static entities that ignore covariation between genes and the multitude of cellular co-signals that determine transcription. In this work, we developed computational approaches that capture gene programs driven by cytokine signaling using single-cell gene expression data. Specifically, we used factor analysis algorithms, guided by gene sets of cytokine targets, to decompose single-cell expression matrices into collections of cytokine-induced gene programs. We applied this approach to the recent Immune Dictionary dataset and human COVID-19 atlases for 31 cytokines. We recapitulated known disease-associated cytokine signals and predicted cell-type-specific cytokine responses. Moreover, we uncoupled primary and secondary cytokine signals induced due to in vivo treatment in the Immune Dictionary. Due to the quantitative nature of our inference, we could also measure interactions of different cytokine signals in sub-populations of cells. With this we identified similarly acting co-signals in tumor associated macrophages from pancreatic and lung cancers. We aim to provide a framework for interpreting complex cytokine signals in single-cell data that can be used to dissect tissue biology. Citation Format: Samuel A. Rose, Russell Kunes, Thomas Walle, Suhani Balachandran, Roshan Sharma, Dana Pe'er. Learning contextual determinants of cytokine signaling during immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB342.
Abstract LB258: Automated high-throughput isolation of extracellular vesicles (EVs) and small RNA sequencing profile in serum of breast cancer patients
Authors: Ramin Khanabdali, Scott Zhu, Mathew Moore, Eric Vincent, Gregory Rice
Journal: Cancer Research (2025)

Abstract Introduction: The molecular profiling of EVs is represents a promising approach for identifying disease-specific biomarkers and developing diagnostic tests for early detection. The clinical translation of EV-based diagnostics into routine clinical practice is hindered by the lack of efficient, reproducible and high-throughput EV isolation and downstream analysis method that can be easily integrated into clinical laboratory workflows. In this study, we used a high-throughput automated bead-based immunoaffinity system (EXO-NET®) to isolate EVs and identify differentially expressed miRNAs from serum samples obtained from women diagnosed with breast cancer to identify EV-associated biomarkers for earlier detection of breast to improve disease prognosis. Methods: EVs were isolated from 500 µl of serum obtained from women diagnosed with breast cancer (I, II, III, IV n=12 per stage) and age matched normal healthy women (n=48) using EXO-NET on high-throughput automated KingFisher Apex system. Small RNAs were isolated on the same system using Promega Maxwell® HT miRNA Plasma and Serum kit for small RNA sequencing and RT-PCR analysis. Results: High-throughput EVs isolation and their associated miRNAs from 96 serum samples was conducted in less than 2 hours. Small RNA seq analysis identified top 50 significantly differentially expressed miRNAs (log2 =2, p &amp;lt; 0.01) between normal healthy women and women diagnosed with breast cancer. Data modelling including GO and KEGG pathway analysis identified molecular pathways associated with breast cancer and EV compartments. Conclusion: We have established an efficient, reproducible and fit-for-purpose high-throughput automated system for the isolation of EVs and the analysis of associated RNAs and proteins. This system shows great potential for facilitating the translation of EV diagnostics into routine clinical practice. Citation Format: Ramin Khanabdali, Scott Zhu, Mathew Moore, Eric Vincent, Gregory Rice. Automated high-throughput isolation of extracellular vesicles (EVs) and small RNA sequencing profile in serum of breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB258.
Abstract SY28-01: The paradox of YAP/TAZ in cancer biology
Authors: Georg Halder
Journal: Cancer Research (2025)

Abstract YAP and TAZ, transcriptional co-activators and the downstream effectors of the Hippo pathway, are often hyperactivated in diverse cancers where they promote tumor growth. Inhibiting the activity of YAP/TAZ is thus an attractive strategy for the treatment of cancer. However, our findings challenge the idea that YAP/TAZ are simply tumor-promoting. Studying mouse models of liver cancer, we found that YAP/TAZ activity in peritumoral hepatocytes exerts a tumor-suppressive function. While deleting Yap/Taz in tumor cells led to tumor regression, deleting Yap/Taz in peritumoral hepatocytes unexpectedly accelerated tumor growth. Even more strikingly, tumor cells no longer required YAP/TAZ when surrounded by Yap/Taz mutant hepatocytes. These results cannot be explained by a simple mechanism whereby YAP/TAZ directly (cell autonomously) promote the proliferation and survival of tumor cells. Rather, they imply that YAP/TAZ act through a non-cell autonomous mechanism of cell competition, whereby cells with higher YAP/TAZ activity outcompete cells with lower levels. Consequently, experimental hyperactivation of YAP in peritumoral hepatocytes triggered tumor regression. We thus propose that YAP/TAZ activity dictates cellular “fitness”: YAP/TAZ are tumor promoting when higher in tumor cells, but tumor suppressing when higher in tumor-surrounding cells. These findings shift our understanding of YAP/TAZ in cancer: rather than being purely oncogenic, their activity in normal cells can lead to the suppression of tumor growth. These effects raise critical questions for YAP/TAZ-targeted therapies, suggesting that inhibiting YAP/TAZ indiscriminately may, in some contexts, accelerate tumor progression rather than suppress it. Citation Format: Georg Halder. The paradox of YAP/TAZ in cancer biology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY28-01.
Abstract SY27-01: Mitochondria function in normal and cancer cells
Authors: Navdeep S. Chandel
Journal: Cancer Research (2025)

Abstract Mitochondrial respiratory chain (RC) activity plays a crucial role in the proliferation of various cell types in vivo within the tumor microenvironment, especially in cancer cells, CD4+ and CD8+ T cells, and endothelial cells. This activity is vital for the production of ATP, which is essential for energy metabolism, and for the biosynthesis of key macromolecules. The mitochondrial respiratory chain is integral to the oxidative tricarboxylic acid (TCA) cycle, which generates intermediates that are used in anabolic pathways to synthesize lipids, proteins, and nucleotides—critical components for cell growth and division. However, the role of mitochondrial respiration is more complex in certain proliferating cells within tumor microenvironment, such as regulatory T cells (Tregs) and stem cells. In these cells, mitochondria are not as critical for the general process of cell proliferation but instead play a pivotal role in determining cell fate and function. Mitochondria influence these processes through various signaling mechanisms that affect how these cells differentiate and carry out their specialized functions. I will discuss how the mitochondrial respiratory chain functions as an anabolic engine that drives the proliferation of cancer cells, CD4+ and CD8+ T cells, and endothelial cells. I will also discuss how mitochondria act as central hubs that integrate metabolic signals to regulate the fate and function of Tregs and stem cells in vivo, highlighting the distinct yet interconnected roles mitochondria play in different cell types. Citation Format: Navdeep S. Chandel. Mitochondria function in normal and cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY27-01.
Abstract LB465: Inhibition of serotonin biosynthesis and tyrosine kinases suppresses tumor growth of neuroendocrine neoplasm
Authors: Dane H. Tow, Maclain Ridder, Catherine G. Tran, Guiying Li, Courtney A. Kaemmer, Aswanth H. Mahalingam, Anguraj Sadanandam, Douglas R. Spitz, Chandrikha Chandrasekaran, Carlos H.F. Chan, Joseph S. Dillon, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po H. Ear
Journal: Cancer Research (2025)

Abstract Small bowel neuroendocrine tumors (SBNETs) originate from enterochromaffin cells in the intestine which synthesize and secrete serotonin. SBNETs express high levels of tryptophan hydroxylase 1 (Tph1), a key enzyme in serotonin biosynthesis. Patients with high serotonin level may develop carcinoid syndrome, which can be treated with somatostatin analogues and the Tph1 inhibitor telotristat ethyl (TE) in severe cases. Although the active drug TE can efficiently reduce serotonin levels, its effect on tumor growth is unclear. This study determined the effect of serotonin inhibition on tumor growth in vitro and in vivo. The levels of Tph1 in various neuroendocrine neoplasms (NENs) were determined and the biological effects of Tph1 inhibition using genetic and pharmacologic approaches was tested. Gene and protein expression analyses were performed on patient tumors and cancer cell lines. shRNAs targeting TPH1 were used to create stable knockdown in BON cells. Control and knockdown lines were assessed for their growth rates in vitro and in vivo, angiogenesis potential, serotonin levels, endothelial cell tube formation, tumor weight, and tumor vascularity. TPH1 is highly expressed in SBNETs and many cancer types. TPH1 knockdown cells and TE treated cells showed similar growth rates as control cells in vitro. However, TPH1 knockdown cells formed smaller tumors in vivo and tumors were less vascularized. Although Tph1 inhibition with TE showed no effect on tumor cell growth in vitro, Tph1 inhibition reduced tumor formation in vivo. The combination of TE andcabozantinib, an effective tyrosine kinase inhibitor for NET, showed further improvement of tumor inhibition. Serotonin inhibition in combination with other therapies is a promising new avenue for targeting metabolic vulnerabilities in NENs. Citation Format: Dane H. Tow, Maclain Ridder, Catherine G. Tran, Guiying Li, Courtney A. Kaemmer, Aswanth H. Mahalingam, Anguraj Sadanandam, Douglas R. Spitz, Chandrikha Chandrasekaran, Carlos H.F. Chan, Joseph S. Dillon, Dawn E. Quelle, Andrew M. Bellizzi, James R. Howe, Po H. Ear. Inhibition of serotonin biosynthesis and tyrosine kinases suppresses tumor growth of neuroendocrine neoplasm [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB465.
Abstract LB438: Discovery of a potent and selective pan-TEAD PROTAC directly targeting TEAD-YAP interaction with durable degradation activity
Authors: Kehao Zhao, Wenchao Lu, Linghui Cao, Yuhang Liu, Yufang Shi, Jian Chen, Yong Zhang
Journal: Cancer Research (2025)

Abstract The Hippo signaling pathway is crucial for regulating numerous biological processes, and its dysregulation is associated with the development of various diseases. As a key effector of this pathway, the TEAD transcription factor interacts with its downstream co-activators YAP and TAZ when Hippo signaling is suppressed, thereby regulating genes involved in cell proliferation and apoptosis. While much research has focused on inhibiting TEAD's palmitoylation and disrupting its interaction with YAP, relatively few studies have explored TEAD-degrading agents. To address this gap, we designed and synthesized a series of heterobifunctional degraders targeting TEADs. Notably, the most prominent compound KG-FP-003 exhibited potent degradation activity, sustained for up to 7 days, and antiproliferative effects at nanomolar concentrations in MSTO-211H cells (lacking functional LATS1/2) and NCI-H226 cells (deficient in NF2), which is to our knowledge, the most effective TEAD degraders. Proteomic analysis revealed significant degradation of TEAD1 and TEAD4 in NCI-H226 cells and A172 cells, consistent with HiBiT assays. Additionally, using a CRBN-knockout MSTO-211H cell line, we demonstrated that KG-FP-003 promotes CRBN-dependent TEAD degradation in a dose-dependent manner. Concomitant with the loss of TEAD, we observed significant alternation of downstream transcription networks. Further studies revealed that KG-FP-003 was effective across a wide range of cell lines beyond mesothelioma. Its sensitivity profile correlates with the dependency scores of TEAD1,YAP1,JUN and TP53BP2. Moreover,KG-FP-003 significantly reduced the expression of key YAP target genes such as CYR61 and CTGF in solid tumors which outperforms known TEAD LBP inhibitors and PPI inhibitors in terms of antiproliferative activity. In summary, KG-FP-003 is a promising candidate for advancing the research of YAP-TEAD research and holds great potential for therapeutic development in Hippo pathway-related diseases. Citation Format: Kehao Zhao, Wenchao Lu, Linghui Cao, Yuhang Liu, Yufang Shi, Jian Chen, Yong Zhang. Discovery of a potent and selective pan-TEAD PROTAC directly targeting TEAD-YAP interaction with durable degradation activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB438.
Abstract SY09-01: Targeting the vagal gut-brain axis: A new approach to combat cachexia
Authors: Xiling Shen
Journal: Cancer Research (2025)

Abstract Cancer-associated cachexia is a complex, incurable syndrome responsible for nearly one-third of cancer-related deaths, driving therapy resistance and increasing mortality in affected patients. In this study, we identify altered vagal tone as a consequence of cancer-induced systemic inflammation in cachectic animal models. This vagal dysregulation disrupts the liver-brain vagal axis, leading to the rewiring of liver protein metabolism through the depletion of HNF4α, a key regulator of liver function. Notably, downregulation of liver HNF4α in wildtype mice induces cachectic phenotypes. Blocking the right cervical vagus nerve—whether through surgical, chemical, or electrical means, including a non-invasive transcutaneous device—slows cachectic progression, mitigates its manifestations, and enhances chemotherapy efficacy, ultimately improving overall well-being and survival. Additionally, this transcutaneous device effectively inhibits vagal hyperactivity in porcine models and humans, paving the way for an upcoming clinical trial to combat cachexia progression in pancreatic cancer patients. Citation Format: Xiling Shen. Targeting the vagal gut-brain axis: A new approach to combat cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY09-01.
Abstract SY07-01: Gain-of-function small molecules to reprogram oncogenic transcription factors
Authors: Sai Gourisankar
Journal: Cancer Research (2025)

Abstract A principle in the development of cancer therapies is that robust death of the malignant cell is critical. Highly effective strategies, such as immunotherapy, engage this principle. Here I will provide the structural and molecular underpinnings for an approach that leverages chemical induced proximity to produce specific cell killing of diffuse large B cell lymphoma, the most common non-Hodgkin’s lymphoma. We developed Transcriptional/epigenetic Chemical Inducers of Proximity (TCIPs): bivalent molecules that redirect epigenetic factors to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6. Acute treatment rapidly reprograms the epigenome to initiate apoptosis and repress c-MYC. The crystal structure of the chemically induced complex of the histone acetyltransferases p300/CBP and BCL6 reveals how chance interactions between the proteins can be systematically exploited to produce exquisite potency and selectivity. Biophysical, proteomic, and genomic experiments demonstrate a sub-stoichiometric, gain-of-function mechanism. Our findings imply that the malignant function of an oncogenic driver can be systematically exploited using chemically induced proximity to activate robust cell death. Citation Format: Sai Gourisankar. Gain-of-function small molecules to reprogram oncogenic transcription factors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr SY07-01.