Periodic Reporting for period 4 - SCIPER (Studying Cancer Individuality by Personal and Predictive Drug Screening and Differential OMICs)
Okres sprawozdawczy: 2023-05-01 do 2024-04-30
In the ERC-StG “SCIPER” project, we have studied the molecular and cellular processes that influence how cancer patients respond to possible treatments. We have done so by combining image-based drug screening in patient biopsies (a technique we call “Pharmacoscopy”) with molecular profiling of those same biopsies and matched patient data, across three clinical studies. The three clinical studies were designed to push the development of our Pharmacoscopy technology from blood cancers (in a study on multiple myeloma study), to fluid biopsies of solid tumors (so called malignant serous effusions), to a fully solid tumor study, specifically the primary brain tumor glioblastoma, thus ensuring we broaden both the technical scope and clinical applicability of Pharmacoscopy.
Our results have led to a better understanding of the molecular and cellular systems that drive people’s response to treatment, and have enabled us to develop complex cellular assays that predict how patients will respond to their treatments and that help identify novel treatment options for individual patients.
The Overall Goals of the SCIPER project were defined as follows:
1. To identify regulatory principles governing drug response variability among cancer patients.
2. To better understand and be able to predict treatment responses of late-stage cancer patients.
Our results, published in Nature Cancer (multiple myeloma), in press at Nature Medicine (glioblastoma), and accepted in principle at Nature Communications (malignant serous effusions), have pushed our understanding of patient variability and cancer heterogeneity, have driven technological developments, and are at the basis for further interventional clinical trials, evidence of the direct possible impact the project results may have on improving patient lives.
Our results have led to a better understanding of the molecular and cellular systems that drive people’s response to treatment, and have enabled us to develop complex cellular assays that predict how patients will respond to their treatments and that help identify novel treatment options for individual patients.
The Overall Goals of the SCIPER project were defined as follows:
1. To identify regulatory principles governing drug response variability among cancer patients.
2. To better understand and be able to predict treatment responses of late-stage cancer patients.
Our results, published in Nature Cancer (multiple myeloma), in press at Nature Medicine (glioblastoma), and accepted in principle at Nature Communications (malignant serous effusions), have pushed our understanding of patient variability and cancer heterogeneity, have driven technological developments, and are at the basis for further interventional clinical trials, evidence of the direct possible impact the project results may have on improving patient lives.
We have initiated and completed three parallel integrated functional and molecular profiling studies, focusing on (1) Multiple Myeloma, (2) Fluid Biopsies, and (3) Glioblastoma. Recapitulating the key findings for each:
Multiple Myeloma (Kropivsek et al., Nature Cancer, 2023)
Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.
Malignant Serous Effusions (Wegmann et al., Nature Communications, 2024, accepted in principle)
Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.
Glioblastoma (Lee et al., Nature Medicine, 2024, in press)
Glioblastoma, the most aggressive primary brain cancer, has dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we here systematically screen repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling >2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of >1 million compounds with high patient validation accuracy. Deep multi-modal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the antidepressant Vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.
As such, the ERC study is completed, and the last publications will appear online in the next weeks.
Beyond the (open access) publications and preprints (e.g. https://www.biorxiv.org/content/10.1101/2022.10.07.511321v2(odnośnik otworzy się w nowym oknie)) the results have been disseminated at numerous scientific conferences, including at the AACR Annual Meeting 2024, April 5-10, in San Diego, as well as at the Nobel Symposium "Precision Medicine Transforms Healthcare: A New Trajectory for Research and Innovation", which was held on September 20-22, 2023, Nobel Forum, Stockholm, Sweden, to name a few.
Multiple Myeloma (Kropivsek et al., Nature Cancer, 2023)
Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM.
Malignant Serous Effusions (Wegmann et al., Nature Communications, 2024, accepted in principle)
Personalized treatment for patients with advanced solid tumors critically depends on the deep characterization of tumor cells from patient biopsies. Here, we comprehensively characterize a pan-cancer cohort of 150 malignant serous effusion (MSE) samples at the cellular, molecular, and functional level. We find that MSE-derived cancer cells retain the genomic and transcriptomic profiles of their corresponding primary tumors, validating their use as a patient-relevant model system for solid tumor biology. Integrative analyses reveal that baseline gene expression patterns relate to global ex vivo drug sensitivity, while high-throughput drug-induced transcriptional changes in MSE samples are indicative of drug mode of action and acquired treatment resistance. A case study exemplifies the added value of multi-modal MSE profiling for patients who lack genetically stratified treatment options. In summary, our study provides a functional multi-omics view on a pan-cancer solid tumor cohort and underlines the feasibility and utility of MSE-based precision oncology.
Glioblastoma (Lee et al., Nature Medicine, 2024, in press)
Glioblastoma, the most aggressive primary brain cancer, has dismal prognosis, yet systemic treatment is limited to DNA-alkylating chemotherapies. New therapeutic strategies may emerge from exploring neurodevelopmental and neurophysiological vulnerabilities of glioblastoma. To this end, we here systematically screen repurposable neuroactive drugs in glioblastoma patient surgery material using a clinically concordant and single-cell resolved platform. Profiling >2,500 ex vivo drug responses across 27 patients and 132 drugs identified class-diverse neuroactive drugs with potent anti-glioblastoma efficacy that were validated across model systems. Interpretable molecular machine learning of drug-target networks revealed neuroactive convergence on AP-1/BTG-driven glioblastoma suppression, enabling expanded in silico screening of >1 million compounds with high patient validation accuracy. Deep multi-modal profiling confirmed Ca2+-driven AP-1/BTG-pathway induction as a neuro-oncological glioblastoma vulnerability, epitomized by the antidepressant Vortioxetine synergizing with current standard-of-care chemotherapies in vivo. These findings establish an actionable framework for glioblastoma treatment rooted in its neural etiology.
As such, the ERC study is completed, and the last publications will appear online in the next weeks.
Beyond the (open access) publications and preprints (e.g. https://www.biorxiv.org/content/10.1101/2022.10.07.511321v2(odnośnik otworzy się w nowym oknie)) the results have been disseminated at numerous scientific conferences, including at the AACR Annual Meeting 2024, April 5-10, in San Diego, as well as at the Nobel Symposium "Precision Medicine Transforms Healthcare: A New Trajectory for Research and Innovation", which was held on September 20-22, 2023, Nobel Forum, Stockholm, Sweden, to name a few.
The ongoing clinical studies and developed technologies of the SCIPER project are all beyond the state-of-the-art, no equivalent studies are reported online. Expected results until the end of the project includes the completion of the goals and objectives as set out in the original proposal.