Abstract 1231: Exploring drivers of variability in patient tumor responses to HIF-2α inhibitor using the Xsphera patient-derived organotypic tumor spheroid (PDOTS) platform

Author: Cui, Chunxiao ; Goldman, Aaron ; Perricone, Michael A. ; Martin, Alyssa

AbstractBackground:The hypoxia-inducible factor 2 alpha (HIF-2α) complex is a critical driver of clear cell renal cell carcinoma (ccRCC), with FDA-approved inhibitor PT2977 (belzutifan) demonstrating promising clinical efficacy. Xsphera’s patient-derived organotypic tumor spheroid (PDOTS) platform offers an innovative ex vivo approach to recapitulate the tumor microenvironment (TME) and assess patient-specific responses to cancer therapeutics. This study highlights how the PDOTS platform can bridge the gap between preclinical and clinical data, providing insights into patient-specific tumor responses and mechanisms of resistance.Methods:Resected patient RCC tumors (n=7) were processed into PDOTS and cultured within a microfluidic device to preserve native TME. Baseline immune cell profiles were characterized using flow cytometry on dissociated single-cell sub-fractions. PDOTS from each patient tumor were treated with the HIF-2α inhibitors PT2977 (7.5-750 ng/mL) and PT2385 (50-5000 ng/mL), or vehicle control. Tumor responses were evaluated at day 3 post-treatment using Hoechst Propidium Iodide (HPI) automated image analysis. RNA was extracted post-treatment, and gene expression was profiled using the NanoString IO360 panel. Integrated analyses of immune cell composition, cytotoxicity, and gene expression were performed to explore potential correlations with response.Results:Cytotoxicity: PT2385 induced dose-dependent cytotoxicity, in 4 of 7 samples (57%), while PT2977 demonstrated activity in 2 of 7 (28%) patient tumors without a clear dose-response relationship. Immune Profiles: No significant associations were observed between baseline immune cell composition and tumor response. Gene Expression: Preliminary NanoString analysis revealed distinct gene expression changes in responsive versus non-responsive tumors. Responsive tumors exhibited downregulation of pro-tumorigenic pathways, including cell proliferation and G2M checkpoint-related genes, relative to controls. Interestingly, markers associated with myeloid cells, such as CD163 and LILRB4, were elevated in responsive tumors following treatment, but remained unchanged in non-responsive tumors.Conclusions:Xsphera’s PDOTS platform effectively mirrors the clinical response rates to HIF-2α inhibitors, offering actionable insights into tumor variability and resistance mechanisms. By combining cytotoxicity, immune profiling, and transcriptomic analyses, the PDOTS platform provides a robust predictive and exploratory tool for oncology drug development. These findings underscore the utility of this platform in tailoring therapeutic strategies for ccRCC and other cancer types.Citation Format:Alyssa Martin, Chunxiao Cui, Aaron Goldman, Michael A. Perricone. Exploring drivers of variability in patient tumor responses to HIF-2α inhibitor using the Xsphera patient-derived organotypic tumor spheroid (PDOTS) platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1231.

21 Apr 2025·Cancer Research

Abstract 6490: Patient-derived organotypic tumor spheroids (PDOTS) optimize donor selection in allogenic cell therapy development

Author: Bhise, Ketki ; Goldman, Aaron ; Munnik, Sabrina D. ; Dumitru, Raluca ; Patel, Sinal ; Lopez, David C. ; Khardenavis, Kirti ; Hagee, Danielle ; Attardo, Anthony ; Cui, Chunxiao ; Martin, Alyssa ; Moiset, Gemma ; Perricone, Michael ; Basheer, Wassim

AbstractIntroduction:Donor-to-donor variability significantly impacts the process development of cell therapies for cancer. Characterizing the donor-specific functional variances enables donor selection for successful cell therapy development. Ex vivo human models provide unique opportunities to evaluate the functionality of cell therapies in the patient’s native tumor microenvironment (TME). Here, using the Xsphera human tumor system, we assessed the specificity, migration, anti-tumor efficacy, and immune modulation of CAR-T cells from different donors to identify the optimal donor characteristics.Methods:HER2-targeting CAR-T cells were generated from the peripheral blood mononuclear cells (PBMCs) of two healthy donors (CAR-D1 and CAR-D2). HER2+ (ZR-75-30) and HER2- (MDA-MB-468) cell lines were used to generate tumor spheroids. Fresh tumor samples collected from patients with ovarian cancer were partially dissociated into spheroids (PDOTS) ranging from 40-100 µm. Tumor spheroids and PDOTS were loaded into microfluidic devices containing extracellular matrix (ECM) and exposed to CAR-D1 and/or CAR-D2. CAR-T cell migration, proliferation and anti-cancer efficacy were measured and quantified using image-based analysis. RNA transcription was analyzed via NanoString to study tumor response and immune modulation.Results:Both CAR-D1 and CAR-D2 showed time-dependent tropism through the ECM towards HER2+ tumor spheroids, but not HER2- tumor spheroids. Increased cytotoxicity was observed in HER2+ tumor spheroids with both CAR-T cells, with CAR-D2 showing greater cytotoxicity. CAR-D1 also induced off-target tumor killing in HER2- spheroids, which was not observed in CAR-D2. Nanostring analysis revealed higher cytotoxic signals in CAR-D1, whereas CAR-D2 showed higher antitumor cytokine signaling in HER2+ tumor spheroids and lower anti-tumor activity in HER2- tumor spheroids. In PDOTS derived from ovarian patient tumors (N=3), CAR-D2’s cytotoxic effect appeared to be correlated with tumor cells’ HER2 expression levels. In high HER2 PDOTS, CAR-D2 led to downregulation of tumor-related genes (ERBB2/HIF1A/EPCAM/EGFR), upregulation of CAR-T activation associated genes (IFNg/GZMB/PRF1/CXCL9/CXCL10/IL1A), and increased CD8 T cell abundances (CD8A/CD8B). In summary, CAR-D2 showed higher target specificity, slower ECM migration, faster spheroids uptake, greater anti-tumor efficacy, and lower off-target cytotoxicity than CAR-D1. Its efficacy in PDOTS appeared to be HER2 expression dependent.Conclusion:The use of Xsphera’s platform to study cell therapies provides a valuable tool for uncovering donor-to-donor variability by differentiating the variability in performance of CAR-T cells derived from different donors. This unique approach will support optimal donor selection and accelerate cell therapy development.Citation Format:Chunxiao Cui, Raluca Dumitru, Danielle Hagee, Anthony Attardo, Kirti Khardenavis, Wassim Basheer, Sabrina D. Munnik, David C. Lopez, Gemma Moiset, Ketki Bhise, Sinal Patel, Alyssa Martin, Michael Perricone, Aaron Goldman. Patient-derived organotypic tumor spheroids (PDOTS) optimize donor selection in allogenic cell therapy development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6490.

01 Dec 2024·Non-coding RNA Research

Ferroptosis contributes to the progression of female-specific neoplasms, from breast cancer to gynecological malignancies in a manner regulated by non-coding RNAs: Mechanistic implications

Review

Author: Bonyadi, Mojtaba ; Nabavi, Noushin ; Klionsky, Daniel J ; Reiter, Russel J ; Aref, Amir Reza ; Hushmandi, Kiavash ; Salimimoghadam, Shokooh ; Saadat, Seyed Hassan

Ferroptosis, a recently identified type of non-apoptotic cell death, triggers the elimination of cells in the presence of lipid peroxidation and in an iron-dependent manner. Indeed, ferroptosis-stimulating factors have the ability of suppressing antioxidant capacity, leading to the accumulation of reactive oxygen species (ROS) and the subsequent oxidative death of the cells. Ferroptosis is involved in the pathophysiological basis of different maladies, such as multiple cancers, among which female-oriented malignancies have attracted much attention in recent years. In this context, it has also been unveiled that non-coding RNA transcripts, including microRNAs, long non-coding RNAs, and circular RNAs have regulatory interconnections with the ferroptotic flux, which controls the pathogenic development of diseases. Furthermore, the potential of employing these RNA transcripts as therapeutic targets during the onset of female-specific neoplasms to modulate ferroptosis has become a research hotspot; however, the molecular mechanisms and functional alterations of ferroptosis still require further investigation. The current review comprehensively highlights ferroptosis and its association with non-coding RNAs with a focus on how this crosstalk affects the pathogenesis of female-oriented malignancies, from breast cancer to ovarian, cervical, and endometrial neoplasms, suggesting novel therapeutic targets to decelerate and even block the expansion and development of these tumors.

News (Medical) associated with Xsphera Biosciences, Inc.

14 Nov 2023

·www.biospace.com

Xsphera Biosciences and NEX-I Collaborate to Advance Oncology Drug Research

Boston, MA – Xsphera Biosciences, a leading biotechnology company specializing in ex vivo testing of oncology therapeutics on patient-excised tumor tissue, is pleased to announce the formalization of a Memorandum of Understanding (MOU) with NEX-I, a Seoul-based pioneer in immune-oncology therapeutics. This partnership represents a significant step forward in oncology drug research and development. At the heart of this partnership lies Xsphera's innovative technology, exclusively licensed from the Dana-Farber Cancer Institute. Xsphera’s technology maintains each patient’s tumor microenvironment in an ex vivo platform directly from a fresh excisional tumor biopsy. Over the past year, Xsphera has played a pivotal role in advancing NEX-I’s pipeline by assessing the performance of NEX-I mono and combination therapies on patient tumor samples. Additionally, the companies have leveraged Xsphera’s cloud analytics platform to jointly explore molecular pathways modulated by the multiple therapeutic treatments, aiming to comprehend the mechanisms of action and resistance for each treatment across a diverse set of patient samples. NEX-I is advancing the development of 'NXI-101', a notable first-in-class antibody drug targeting 'ONCOKINE-1', a factor produced by cancer cells that contributes to the resistance of cancer cells to cancer immunotherapy. With treatments like NXI-101 designed to counter these resistance factors, NEXI aims to bolster the efficacy of cancer immunotherapy. Furthermore, NEX-I is diligently working to expedite its entry into global clinical markets. Stephen Remondi, CEO of Xsphera Biosciences, remarked, "This MOU underscores our shared commitment to deepen our collaboration. We are excited to further our understanding of immune modulation in response to NEX-I therapeutics as well as to discover new therapeutic targets in oncology that is enabled by comparing the modulated responses of different therapeutics on tumor tissue from the same patient. " Importantly, this partnership is set to deliver tangible benefits to cancer patients by tailoring treatments to their unique biological responses, thereby improving treatment outcomes and personalizing the battle against cancer." CEO, Kyoung Wan Yoon, stated, “NXI-101 is on the verge of entering clinical trials next year. On top of our animal data, validating the efficacy and mechanism of NXI-101 through our collaborative research with Xsphera increases our likelihood of clinical success, and will deliver real-world value to patients. Furthermore, through this research collaboration, we aim to verify the possibility of developing companion diagnostic biomarkers for the NXI-101 treatment and accelerate the pace of technological and business growth globally." About Xsphera Biosciences: Xsphera Biosciences is a biotechnology company dedicated to bridging the translational gap between animal models and human clinical trials for oncology therapeutics. Through collaboration with Dana-Farber, Xsphera has developed a revolutionary fresh human tumor tissue-based platform that enables the assessment of therapeutic efficacy across various cancer indications and drug modalities. Integrating this ex vivo biology capability with its AI-powered cloud analytics platform, Xsphera can reveal the underlying mechanisms of action and resistance in the tumor microenvironment, providing invaluable insights into human biology and clinical trial strategy. For more information, please visit the Xsphera website at . About NEX-I: NEX-I is breaking ground in the fight against cancer with its next-generation therapies targeting immunotherapy-resistant cancers. Leveraging its proprietary platform, NEX-I has developed robust models for immunotherapy-refractory cancers to analyze their characteristics and identify novel therapeutic targets comprehensively. This unique and dedicated research has led to the discovery of a series of soluble targets, ONCOKINE, which highly expresses and plays a critical role in refractory cellular mechanisms through the proprietary screening platform. NEX-I proposes a new standardized solution to inhibit cancer cell growth and metastasis by suppressing them. Learn more at . A copy of the White Paper describing NXI-101 and the results from Xsphera platform can be found here: For further information, please contact: Xsphera Biosciences Inc. Kazuhito Ishikawa Vice President, Sales and Business development kazu@xspherabio.com

Immunotherapy

100 Deals associated with Xsphera Biosciences, Inc.

100 Translational Medicine associated with Xsphera Biosciences, Inc.

Corporation Tree

Boost your research with our corporation tree data.

view full example data

Pipeline

Pipeline Snapshot as of 12 May 2025

The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

Preclinical

Current Projects

Drug(Targets)	Indications	Global Highest Phase

NXI-101 ( TCTP )	Solid tumor More	Preclinical
LRK-A ( PIP4K2C )	Colorectal Cancer More	Preclinical

Deal

Boost your decision using our deal data.

view full example data

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Profit

Explore the financial positions of over 360K organizations with Synapse.

view full example data

Grant & Funding(NIH)

Access more than 2 million grant and funding information to elevate your research journey.

view full example data

Investment

Gain insights on the latest company investments from start-ups to established corporations.

view full example data

Financing

Unearth financing trends to validate and advance investment opportunities.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis