The main area of expertise of the Breast Cancer Group led by Cristina Saura is clinical research focused on drug development and associated translational research. In addition to high patient recruitment in our studies, we also play a leading role in many of the clinical trials that we run. This enables us to have a direct impact in applying translational data to guide and accelerate drug development:
Our Melanoma and other skin tumors Group is led by Eva Muñoz. She has actively participated in several phase I, II and III trials focused on melanoma and other skin tumors to study various emerging therapies for the treatment of these diseases. This group leads it own research program incorporating clinical investigators, dermatologists and cancer investigators at VHIO.
The team’s studies focus on new target therapies and resistance to immunotherapy by conducing purely translational research centered on melanoma, skin squamous and basocelular carcinoma resistance acquisition and disease progression. Their efforts also center on mapping new therapeutic avenues, follow up standards and identifying biomarkers for a more precise treatment selection matched to the specificities of our patients.
We focus on proof-of-concept and proof-of-mechanism trials with targeted therapies, with particular emphasis on cell signaling, cancer stem cells, and immuno-oncology. These include first-in-human studies of targeted therapies, rational combinations of targeted therapies, biomarker-driven trials, and studies in molecularly selected populations.
We link clinical research at the Research Unit for Molecular Therapy of Cancer (UITM) –”la Caixa”, with different areas of investigation carried out at VHIO, following a truly translational model. For selected projects, we match molecular biology and optimal tumor models with pharmacology and innovative clinical research by involving VHIO scientists in our trials (biomarker development, profound understanding of mechanisms of action and resistance).
We have collaborated with VHIO’s Molecular Oncology and Cancer Genomics Groups, led by Paolo Nuciforo and Ana Vivancos, as well as Rodrigo Dienstmann, PI of our ODysSey Group, together with Susana Aguilar and Jenifer Gonzalez, to perform molecular analysis of patients’ tumors. This enables us to select the optimal treatment for our patients with the experimental therapies available in our portfolio of clinical trials.
Importantly, in relation to precision oncology, VHIO is a founding member of both the WIN (Worldwide Innovative Networking in personalized cancer medicine), and the Cancer Core Europe (CCE), consortia. Both are non-governmental organizations that connect international (WIN) and/or European (CCE) cancer centers, including VHIO, to advance cancer diagnostics and therapeutics.
This year, our group and VHIO’s UITM, have continued to lead the Basket of Baskets (BoB) trial, securing funding to add new modules to the multi-modular trial. This academic study, endorsed by Cancer Core Europe, integrates molecular prescreening, the development of new diagnostic tests such as circulating DNA, with the assessment of targeted therapies in populations of patients who, matched to specific molecular alterations, will be most likely to benefit from these treatments.
Our Early Drug Development Group and Phase I Unit (UITM), continues to establish VHIO as a leading reference in driving drug development and targeted therapies in oncology. Testament to this is the number of patients who entrust us with their care (499 patients enrolled in phase I and basket studies in 2019), the portfolio of different trials available (162 phase I trials including 22 basket studies in 2019), and the novelty of our programs in precision medicine and immunotherapy drug development. This is also evidenced by our leading role in Cancer Core Europe’s Clinical Trials Task Force.
We have also fostered important alliances with the pharmaceutical industry, including this year’s Partner of Choice Initiative with MedImmune, and collaborate closely with other clinical research organizations and academic centers of excellence, as well as companies dedicated to advancing personalized cancer medicine and care.
VHIO’s Experimental Hematology Group conducts translational, pre-clinical and clinical research on hematological neoplasms of both lymphoid and myeloid origin. Our research team is composed of hematologists and biological scientists who work closely together to design, conduct and lead our programs. Our projects are always based on the unmet medical needs identified by hematologists, with the ultimate goal of translating our results to patients by developing early phase clinical trials and defining novel biomarkers to improve diagnosis, prognosis and outcomes.
We aim to provide new therapeutic options for our patients by deciphering the mechanisms involved in the pathogenesis and progression of hematological malignancies. We also conduct pre-clinical studies of new therapeutic proposals for patients diagnosed with hematological malignancies. Our group fosters the definition of new biomarkers in hematology that will lead to a more rational and precise diagnosis, prognosis and treatment of our patients.
Finally, the Hematology Clinical Trials Unit is currently participating in more than 103 clinical studies, including phase I clinical trials (n=25) and first-in-human studies of targeted therapies, both in lymphoid and myeloid malignancies. Last year 146 patients were included in our clinical trials, with 53 patients enrolled in phase I studies.
Main research lines currently focus on:
Our Gastrointestinal and Endocrine Tumors Group has actively participated in the development of molecular therapies targeting altered signaling pathways of colorectal, pancreatic, gastric and neuroendocrine cancers, among others. We have pioneered early phase clinical trials to potentiate novel anti-cancer strategies against GI cancers, as well as translational studies associated to these novel therapeutic approaches, including biomarker discovery.
We focus on seeking out prognostic and predictive factors related to targeted and immune therapies as well as identifying new response and resistance markers. Our group has also made significant progress in validating and developing liquid biopsy technologies, including BEAMing, for the more effective, less invasive monitoring of cancer in real time. Moreover, our research has shown that genomic and transcriptomic profiling are both useful for guiding treatment decision making and improving patient outcomes.
Through our participation in the OPTIMISTICC Grand Challenge -Opportunity To Investigate the Microbiome’s Impact on Science and Treatment In Colorectal Cancer- five-year consortium funded by Cancer Research UK’s Grand Challenge, we are also studying the microbiome and it is role and relevance in the development of colorectal cancer. Within the same collaborative project we have launched a novel prospective cohort, the MICROCOSM cohort, to longitudinally analyze over 2500 patients and how current colon cancer treatments affect the microbiome.
In 2019, we have participated in several clinical and translational research collaborations. Our group was instrumental in the development of clinical research studies that could well be practice changing for the treatment of two gastrointestinal malignancies: 1) colorectal tumors bearing BRAF V600E mutations and 2) gBRCA1/2 mutated pancreatic cancer (see selected papers below).
The CELAC and European Consortium for a Personalized Medicine Approach to Gastric Cancer (LEGACy), funded through the European Union’s Horizon 2020 research and innovation program, launched in 2019. As a member of this project, we coordinate data integration and perform the molecular characterization of study samples. These efforts are led by María Alsina, Medical Oncologist and Clinical Investigator of our group, and Rodrigo Dienstmann, PI of our Oncology Data Science (ODysSey) Group.
Also funded by the European Union’s Horizon 2020 research and innovation programme, NoCanTher–Nanomedicine upscaling for early clinical phases of multimodal cancer therapy is a multi-center–Consortium represents an important forward step in in utilizing nanoparticles than can better target and more precisely combat cancer cells. During its 8th General Assembly in London (UK) this year, researchers discussed the project's progress and defined the final steps for reaching the clinical setting, under the leadership of our group, expected to start during the next year.
Reflected by publications in some of the most prestigious scientific titles in 2019, our group has both directed and collaborated in important studies, just some of which include:
Encorafenib, Binimetinib, and Cetuximab in BRAF V600E-Mutated Colorectal Cancer (Kopetz S, et al. N Engl J Med. 2019). For more information about this study which was led by our Director, Josep Tabernero, please see his Foreword.
Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer (Golan T, et al. N Engl J Med. 2019).
Metastatic pancreatic cancer is particularly refractory to treatment. Current standard-of-care first-line treatments are associated with a median progression-free survival of approximately 6 months, and fewer than 10% of patients are alive 5 years after the initial diagnosis. In POLO study, co-authored by our PI, Teresa Macarulla, patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. Among patients with this germline BRCA mutation and metastatic pancreatic cancer, results showed that progression-free survival was longer with maintenance olaparib than with placebo.
Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE - a global phase III study (Yoshino T, et al. Ann Oncol. 2019).
The RAISE study, led by Josep Tabernero, showed that the addition of ramucirumab to FOLFIRI improved patient outcomes, regardless of RAS/RAF mutation status, and tumor sidedness. Ramucirumab treatment provided a numerically substantial benefit in BRAF-mutated tumors.
Second-line treatment with ramucirumab+FOLFIRI improved overall survival (OS) versus placebo+FOLFIRI for patients with metastatic colorectal carcinoma (CRC). Post hoc analyses of RAISE patient data examined the association of RAS/RAF mutation status and the anatomical location of the primary CRC tumour (left versus right) with efficacy parameters.
Phase I/II Trial to Evaluate the Efficacy and Safety of Nanoparticle Albumin-Bound Paclitaxel in Combination With Gemcitabine in Patients With Pancreatic Cancer and an ECOG Performance Status of 2. Macarulla T, et al. J Clin Oncol. 2019.
Led by our PI, Teresa Macarulla, this study was designed to evaluate the efficacy and tolerability of different gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel (GA) dosing regimens in patients with metastatic pancreatic ductal adenocarcinoma (PDAC) and a poor PS. NAB-paclitaxel administered at different doses in combination with gemcitabine on days 1, 8, and 15 every 28 days is well tolerated and results in acceptable safety and efficacy in patients with metastatic pancreatic ductal adenocarcinoma and a poor Karnofsky performance status (PS). Moreover, gemcitabine plus nanoparticle albumin-bound (NAB) paclitaxel GA significantly improved survival compared with gemcitabine alone in patients with PDAC and a PS of 70% or greater. Due to the low number of patients with reduced PS, the efficacy of this regimen in fragile patients remains unclear.
We are dedicated to advancing clinical and translational research against cancer and have extensive experience and expertise in treating various neoplasms. We design and develop clinical trials for genitourinary malignancies at different stages of disease in collaboration with urologists and radiation therapists.
During 2019 we continued to consolidate our expert Prostate Task Force. By closely connecting clinical and translational researchers at VHIO and the Vall d’Hebron Research Institute (VHIR), we have initiated translational projects focused on prostate cancer. We are also doing the same for kidney cancer in pursuit of similar goals in collaboration with other partners including Biomedical Research Institute of Bellvitge (IDIBELL).
Over recent years, several advances have been reported in the more effective treatment of GU malignancies. Immunotherapy (IO) is proving increasingly important against bladder and kidney cancers. Concerning the latter, immune-based therapies in combination with others or paired with antiangiogenics is considered the new standard treatment for first-line therapy. Both approaches have proven more effective compared with antiangiogenic therapy alone.
In bladder cancer immunotherapy has also been shown as superior to chemotherapy in second line and in first-line for ineligible patients. It has recently been shown that immunotherapy in combination with concurrent chemotherapy or as maintenance after 4/6 cycles of chemotherapy in first-line improves progression-free survival (PFS).
Our group –along with others- has observed that immunotherapy could also be effective for certain subgroups of patients with castration-resistant prostate cancer. We are currently participating in phase I studies to assess immune-based cancer medicines for the treatment of this patient population.
We have also participated in various clinical trials using checkpoint inhibitors for the adjuvant treatment of bladder and kidney cancers with high risk of recurrence. Working closely with our Vall d’Hebron University Hospital’s Urology Department and other experts in high-risk tumors, we are currently running studies aimed at improving outcomes for patients with non-muscle- invasive bladder cancer.
We collaborate with various other renowned research centers including the Cleveland Clinic (Ohio, USA), University of California, San Francisco (California, USA). We also participate in studies carried out in partnership with the Gustave Roussy Institute (Paris, France), Barts Health NHS Trust – Hospital (London, UK), and Kantonsspital St. Gallen (Switzerland).
This year we have expanded our translational research program in prostate cancer working alongside VHIO’s Prostate Cancer Translational Research Group, led by Principal Investigator Joaquin Mateo. We have performed 20 biopsies (16 bone and 4 prostate biopsies) and aim to correlate blood samples with these tests.
Our main focus is metastatic castration-resistant prostate cancer and we are working on a project led by Joaquin, entitled: Clinical Qualification of DNA Repair Defects as Biomarkers in Metastatic Prostate Cancer Using Integrated Genomics and Tissue-Based Functional Assays. This research is supported by the US Department of Defense’s (DoD) Congressionally Directed Medical Research Program. Additionally, we are participating in the IRONMAN project lead by the Memorial Sloan Kettering Cancer Center (MSKCC – New York, USA). Led by VHIO we collect patients’ reported outcomes in parallel with serum. This research is supported by Movember and the FERO Foundation.
We are also partnering with VHIO’s Radiomics Group headed by Raquel Perez-Lopez, to analyze MRI alterations in patients who have started hormonal treatments for metastatic prostate cancer and correlate these data with bone biopsies performed in parallel.
This particular project, iPROMET: a study for clinical validation of whole-body diffusion-weighed MRI as a response biomarker of bone metastases in patients with prostate cancer, counts on the combined expertise of a urologist, radio-oncologist, radiologist and medical oncologist to establish a circuit for the systematic metastatic tissue acquisition from prostate cancer patients at our Hospital.
We have also expanded our avatar program for kidney cancer tumors in collaboration with IDIBELL and implanted more than 30 samples. Additionally, we continue to participate in the REVOLUTION project, pREdiction of niVOLUmab acTION metastatic renal cancer patients: Treg function, tumoral access and NK interactions as predictive biomarkers of immunotherapy, supported by TRANSCAN-2 ERA-NET, under the scope of the EU Framework Programme Horizon 2020.
In collaboration with other professionals in neurosurgery and radiation therapy, we lead and develop several multidisciplinary clinical studies and phase I trials in CNS tumors. Additionally, it is thanks to a project with our Gene Expression & Cancer Group led by Joan Seoane, that we continue to develop VHIO’s translational research platform for glioblastoma. We analyze cfDNA in blood and cephaloraquidic liquid for assessing primary CNS tumors and metastases.
Our group also collaborates in a project directed by the European Organisation for Research and Treatment of Cancer (EORTC, Brussels, Belgium), against several tumor types, working on CNS tumors: Cancer Patients for Efficient Clinical Trial Access (SPECTA). The main objective is to screen patients and develop academic clinical trials based on molecular stratification. This initiative is supported by the European Cancer Research Fund (ECRF) and Walgreens Boots Alliance (WBA). We are also active at the national level in a medulloblastoma platform to better define and classify these cancers.
We continue to work closely with the Spanish Sarcoma Group (GEIS) on clinical trials at different stages of disease with emphasis on a histology-tailored design and are currently setting up a translational platform for sarcomas and basic research in partnership with IDIBELL and the Cancer Research Center of Salamanca – CIC (Spain). For GIST tumors we are working with Jonathan Fletcher’s lab at the Brigham and Women’s Hospital (Boston, USA).
Importantly, we have been recognized by the Spanish Ministry of Health as a Spanish National Health System Reference Service (Centros, Servicios y Unidades de Referencia del Sistema Nacional de Salud - CSUR), to treat sarcoma patients. This accreditation enables us to participate in the European References Network (ERN) for sarcoma tumors and other rare diseases.
One of our group members, César Serrano, who carried out a three-year fellowship at the Dana Farber Cancer Institute (Boston, USA), has established an independent line of experimental research on sarcomas. Notably, his translational studies have led to novel treatment strategies against sarcoma, including the design of a phase Ib clinical trial to assess – for the first time in oncology – a rapid-alternation drug schedule of targeted therapies (NCT02164240). In 2019 he set up his own research group, VHIO’s Sarcoma Translational Research.
During this year we have consolidated different clinical trials with new drugs in GIST by leading and participating in phase I-II-III studies. As this report went to print, one of these studies led to the U.S. Food and Drug Administration’s (FDA) January 2020 approval of avapritinib for the treatment of adult patients harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including D842V mutations.
Our Serum Bank now incorporates the majority of tumor types that we study (CNS tumors, GIST; renal cell carcinoma and CRPC), and we will continue to collect samples from our patients.
Dedicated to promoting education and exchange, in 2019 we welcomed six fellows from in (5) and outside (1) of Spain for three-month short stays.
Our clinical research group focuses on gynecological malignancies and the development of novel therapies against these tumor types. We are also members of some of the most relevant societies in gynecological oncology including the Gynecologic Cancer InterGroup (GCIG) for which we are appointed as the Spanish Representative on the Cervical Cancer as well as phase II trial Committees, the Gynecologic Oncology Group (GOG), as the Spanish clinical lead, as well as the European Network of Gynecological Oncology Trial Groups (ENGOT).
Our group contributes to the advancement of the treatment of gynecological malignancies. Over the past few years, we have participated in the development of a number of therapies that constitute the current standard of care in different malignancies. As an example, our PI, Ana Oaknin, is one of the co-authors of the SOLO-1 trial (Olaparib as maintenance therapy in BRCA mut Ovarian Cancer patients) – Moore et al. N Engl J Med. 2018. This clinical trial has changed first line therapy for those patients diagnosed with ovarian cancer harboring a BRCA mutation.
In 2019 we have participated in several important clinical trials that have generated new and compelling data in gynecologic malignancies. As an example, we co-authored a study showing that the addition of veliparib to standard chemotherapy based on paclitaxel/carboplatin, and as maintenance therapy, significantly prolonged progression free survival of all our patients recently diagnosed with high-grade ovarian cancer (Coleman RL et al. N Engl J Med. 2019).
As part of our evolving knowledge on PARPi and mechanisms of resistance, our deep liquid biopsy analysis performed on patients’ blood samples collected during their participation in the ARIEL-2 study, has enabled us to identify BRCA reversion mutations as one of the key players (Lin KK et al. Cancer Discov. 2019).
While metastatic cervical cancer is a devastating disease, over recent years we have succeeded in broadening our therapeutic approaches which have mainly been driven by immunotherapy. We have been studying the role of the anti-PD1 molecule nivolumab in those patients who have progressed after failure to respond to platinum therapy. We have observed encouraging activity in this patient population with a notoriously poor prognosis which certainly warrants further investigation (Naumann RW et al. J Clin Oncol. 2019).
In addition, our Principal Investigator, Ana Oaknin, also serves on the Executive Board as Vice President for the Grupo Español de Investigación en Cáncer de Ovario – GEICO (the Spanish Ovarian Cancer Research Group), and as Faculty of the European Society for Medical Oncology’s (ESMO) Annual Meeting’s Gynecological Tumors Track, for which she was appointed as the Track Chair at the ESMO Congress 2019 (Barcelona, Spain, 27 September-01 October), where she discussed the selected presentations of the Track’s Presidential Symposium.
We focus on the clinical development of PARP inhibitors (PARPi) in early gBRCA1/2 breast cancer and novel combinations in the advanced setting. The consolidation of our collaboration with VHIO’s Experimental Therapeutics Group, led by Violeta Serra, has resulted in a large collection of BRCA1/2-associated patient-derived xenografts (PDX) implanted in athymic mice. We are using these murine models to identify mechanisms of resistance to targeted therapies, identify novel biomarkers, and assess new combinatorial treatments at progression. We have identified a functional biomarker for PARPi sensitivity that has been tested preclinically and in human samples, and we are now collecting samples for a larger clinical validation.
Our group is also interested in unravelling the challenges of implementing the advances in diagnosis of hereditary cancer susceptibility and applying these insights to clinical practice. In partnership with the hereditary cancer program at the Catalan Institute of Oncology (ICO), we are investigating the genetic complexity of hereditary cancer through the multidimensional analysis of a customized panel, as well as the psychological impact in our population. Ongoing research centers on the role of personality traits in predicting the psychological impact of genetic results and the uptake of prevention strategies. We have recently received funding to assess genome-based cancer risk estimation and cancer-risk adapted approaches incorporating polygenic risk score (PRS) analysis. A longitudinal national-based registry of mutation carriers incorporates prospective data for the analysis of health outcomes.
We pursue our interest in the genetic epidemiology of hereditary breast and ovarian cancer (HBOC) in collaboration with Senior Scientist of our group, Sara Gutiérrez-Enríquez. This joint research has shed important light on the characterization of new pathogenic variants in HBOC genes, and provided discriminatory tools to interpret variants of uncertain significance in BRCA genes. Our group is devoted to deciphering the role of intronic, splicing, and missense variants in major HBOC genes and investigate the yield of long-read RNA-seq. Sara Gutiérrez-Enríquez is also independently leading research into predictive genetic and cellular markers for susceptibility to radiotherapy-induced clinical toxicity.
VHIO's ODysSey Group promotes translational research in precision oncology by integrating cancer molecular profiling data with clinical outcomes of oncology patients treated at the Vall d’Hebron University Hospital (HUVH).
To explore big and real-world data, we design and maintain comprehensive clinical-molecular databases and provide operational support to investigators interested in correlative analyses for hypothesis-generation and biomarker validation. We also assist investigators in sample size calculation, clinical trial design and downstream statistical analyses.
Our team also participates in international multi-omic data analyses projects and foster collaborative research in computational oncology. We are dedicated to connecting cancer researchers working on predictive and prognostic modelling, the identification of cancer drivers, molecular subtyping, primary-metastasis heterogeneity, microenvironment signatures and druggability in solid tumors.
Molecular Prescreening Program
In 2019, our group, together with Susana Aguilar and Jenifer Gonzalez, and in collaboration with VHIO's Cancer Genomics Group led by Ana Vivancos, and Molecular Oncology Group, directed by Paolo Nuciforo, have performed tumor molecular profiling in over 1,100 cancer patients as candidates for enrollment in clinical trials. In total, 151 patients were treated with biomarker-matched innovative therapies as a result of this effort.
Interpretation of next-generation sequencing tests and educating clinicians on emerging biomarkers is another of our priority areas. During our Molecular Tumor Board meetings, we promote precision oncology by providing guidance regarding inclusion in early clinical trials with biomarker-guided targeted agents or immunotherapies.
Over the last decade, we have witnessed a revolution in the treatment of metastatic castration-resistant prostate cancer (mCRPC) which is an advanced and lethal form of prostate cancer. A deeper understanding of its underlying biology has led to the development of compounds targeting the androgen signaling pathway and the immune system, as well as taxanes and radiopharmaceuticals.
Despite these advances in more effectively managing mCRPC, it remains a fatal disease resulting in significant morbidity and mortality globally. Arguably, the most critical need in drug development against CRPC is treatment molecular stratification. In parallel efforts must continue to center on identification of robust predictive biomarkers of response and the development of targeted anti-cancer therapies. The advent of these novel treatments has driven tumor evolution towards a shift in the genomic landscape observed in patients with advanced disease.
We embrace a purely comprehensive and integrative approach to research. As such, our group encompasses molecular biology, tumor genomics, clinical trials and computational sciences in order to develop precision medicine strategies to treat advanced prostate cancer based on predictive biomarkers of response.
Defects in DNA repair genes -particularly in double-strand breaks- are present in 20-25% of mCRPC cases, and allow us to study how we can deliver more precise cancer treatment and care. Some of these mutations have prognostic and predictive implications which are crucial in delivering on the promise of personalized medicine in oncology.
We use a range of tools (CRISPR gene editing, shRNA, siRNA and pharmacological inhibitors) to induce loss-of-function of key DNA repair genes in prostate cancer in-vitro models to establish how tumors adapt their DNA repair machinery, and how this is affected by modulation of oncogenic AR signaling. Our interest in cell cycle modulation by DNA damage has also led us to study the senescence-like phenotype observed after exposure to targeted agents, which we hypothesize is a mechanism of drug resistance, and how to target it therapeutically.
Aiming at translating our findings into benefits for patients as rapidly as possible, we study the same genomic and transcriptomic signatures in biopsies from patients with metastatic prostate cancer. In parallel, we collect longitudinal liquid biopsies to study how a tumor evolves during response and progression to targeted agents.
Our research focuses on optimal patient stratification strategies for clinical care, with particular emphasis on combining DNA repair targeting agents with those that inhibit androgen signaling.
VHIO’s Radiation Oncology Group is integrated within the Radiation Oncology Department of the Vall d’Hebron University Hospital (HUVH), and is actively involved in the multidisciplinary treatment of patients with malignant tumors. We also participate either as Principal Investigators or research collaborators in a number of pioneering clinical trials, translational research projects, as well as technology development programs.
In 2019 we have renewed three linacs thanks to a donation received from the Amancio Ortega Foundation. The machines incorporate all the very latest technology and the implementation of these highly complex techniques requires additional expertise from our service, special trainings in order to establish the indications, administration procedures, quality control methods, as well as the implementation of the necessary tools for the measurement of results. These include:
Our Radiomics Group keeps growing; in 2019 Alonso Garcia and Marta Ligero started their PhD programs and Samantha Toinga joined us to carry out her MsC research project on imaging habitats towards evaluating tumor heterogeneity. Kinga Bernatowicz also joined the group as our new Post-Doctoral Scientist. We are also pleased to announce that we are currently recruiting for additional new talents and will soon incorporate another post-doctoral researcher to the group.
Over the last year, we have fostered further collaborations with additional leading imaging research groups including the Computing Vision Centre (CVC–Universitat Autónoma de Barcelona), and cutting-edge centres such as the Bellvitge Institute for Biomedical Research (IDIBELL), in Barcelona, the Institute of Cancer Research (ICR), London, UK, the Netherlands Cancer Institute (NKI), Amsterdam, and the Cancer Research UK (CRUK) Cambridge Institute. In partnership, we have designed various projects for which we have applied for funding through national and international grants.
Continuing our collaboration with VHIO’s Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa” led by Elena Garralda, we have developed a CT-radiomics signature towards better characterizing immunotherapy response (selected as an Oral Presentation at the ESMO Congress 2019, 27 September – 01 October, Barcelona; paper currently under review). Thanks to the support received through an AstraZeneca Proof of Concept Award, we will soon initiate the first prospective study of CT and multiparametric MRI-radiomics to quantify changes in tumor cellularity and vascularization as a biomarker of response to immune checkpoint inhibitors.
We are also delighted to report that the CRIS Cancer Foundation has recently awarded Raquel Perez-Lopez with a Research Talent Award. This will fuel her research aimed at improving cancer patient selection for immunotherapy and better understanding differential responses to immune-checkpoint inhibitors.
Thanks to the support of received from the Carlos III Institute of Health (ISCIII) and the Prostate Cancer Foundation Young Investigator Award, we have started a multi-center prospective study of whole-body diffusion-weighted MRI as a response biomarker of bone metastasis in prostate cancer patients. This study will soon be expanded to include breast cancer patients thanks to funding from La Fundació La Marato de TV3 (PreciMet study).
We have also established interdisciplinary partnerships with various VHIO groups to work together on several translational research projects. Our ethos of team science is key for optimizing imaging and accelerating translational research against cancer.
Focused on applying imaging biomarkers and radiomics to cancer discovery, our efforts center on advancing precision imaging in personalized medicine towards ultimately improving outcomes for cancer patients.
Sarcoma encompasses >70 entities of mesenchymal origin, constituting 1-2% of all cancers. From a biological perspective sarcomas can be classified into two broad categories: genomically simple sarcomas driven by simple genetic alterations, such as translocations or specific activating mutations; and tumors with complex and unbalanced genomic aberrations. Each of these categories includes diverse sarcomas subtypes showing often profound differences in their molecular makeup, course of disease and therapeutic approach.
Our group focuses on the study of sarcomas with oncogenic dependency on specific drivers of disease. Among them, gastrointestinal stromal tumor (GIST) is the most common malignant mesenchymal neoplasm and constitutes a paradigmatic model to study oncogene addiction and identify structural and functional mechanisms for drug response and drug resistance.
Ongoing aim efforts aim at a deeper biological understanding of GIST and other sarcomas in order to advance drug development. One of the major hurdles with a direct impact on patients’ outcomes, concerns the heterogeneity of mechanisms of resistance. Our overarching goal is therefore to identify crucial molecules and signaling mechanisms in GIST biology that can serve as therapeutic vulnerabilities.
We also continue to validate a core set of molecules co-regulated by KIT downstream pathways and identified through extensive whole transcriptome studies across several clinically representative human GIST models. Our group is particularly interested in those with pro-survival function to better understand cellular adaptation to driver inhibition, which may eventually be novel therapeutic targets.
We are as equally interested in performing high-throughput genomic and transcriptomic studies in order to decipher the evolving patterns of resistance in GIST throughout the course of disease, as well as researching liquid biopsy in sarcoma to provide robust evidence that will help to more precisely guide treatment decisions through plasma sequencing.
Our goal is to have a true impact clinically by improving the daily treatment and care of our sarcoma patients. We are proud to report that our Sarcoma Multidisciplinary Unit has been designated as an Expert National Sarcoma Center by the Spanish Ministry of Health, and thus constitutes an optimal setting to translate cancer discovery into true clinical outcomes.
VHIO’s Thoracic Tumors & Head and Neck Cancer Group is dedicated to advancing cancer treatment and care for patients suffering from thoracic malignancies, including lung cancer, mesothelioma and thymic malignancies, and head and neck cancers. We focus on disease prevention, early detection and the more precise diagnosis and staging of disease toward improving clinical outcomes.
Our group strives to match currently available targeted therapies with specific molecular alterations identified in patients, identify molecular mechanisms of acquired resistance, and optimize novel immunotherapy strategies.
For our patients with early-stage thoracic malignancies, we collaborate closely with a multidisciplinary team incorporating thoracic surgeons, radiation therapists, radiologists, pulmonologists, pathologists and biologists. In so doing, we are potentiating several treatment approaches and modalities. Given that our patients can suffer from severe symptoms we are also deeply committed to ameliorating clinical outcomes by working in tight connectivity with professionals across other disciplines.
Precision medicine for the treatment advanced lung cancer is no longer an ambition. It is a guiding principle. We establish molecular determinants of disease in individual tumors and circulating-free DNA (cfDNA) by liquid biopsy, to more effectively tailor therapies to the specificities of each patient’s disease.
For patients with head and neck tumors we work alongside expert surgeons, radiotherapists, radiologists, pathologists, and nutritionists, and also lead a clinical trial program to assess novel immunotherapeutics and targeted agents in this particular setting.
Immune-based strategies have a role in the treatment algorithm for the management of non-small cell lung cancer; a number of protocols are now ongoing at our Research Unit for Molecular Therapy of Cancer (UITM) – ”la Caixa”. We contribute to VHIO’s early clinical drug development efforts, led by Elena Garralda, and also manage other less common thoracic malignancies including head and neck cancer, small-cell lung cancer, mesothelioma, thymoma and neuroendocrine tumors.
The immune system can recognize, hone in on and eliminate cancer. Through multiple mechanisms however, tumors can evade and dodge the immune response. Immunotherapies against cancer exploit the immune system to more effectively attack disease. Clinical studies have shown that immune checkpoint inhibitors and T cell-based therapies can mediate tumor regression in cancer patients with metastatic disease. Thus, in addition to surgery, radiation therapy and chemotherapy, immunotherapy is increasingly representing the fourth pillar of anti-cancer therapy across a variety of tumor types.
Despite encouraging antitumor responses, currently only a fraction of patients treated with immune-based therapies respond and some unfortunately report autoimmune-related adverse events. There is therefore a critical need to develop and personalize these promising treatments.
To do so, and thanks to the support received from the BBVA Foundation's Comprehensive Program of Cancer Immunotherapy & Immunology (CAIMI) at VHIO, we study mechanisms of response, toxicity and resistance to cancer immunotherapeutics in patients at the Vall d’Hebron University Hospital (HUVH). We aim to identify biomarkers of response in liquid biopsies.
One correlative biomarker described to-date is mutation burden. Tumor-specific somatic mutations are optimal targets for cancer immunotherapy and render tumors immunogenic; some of these can bind to the patients’ human leukocyte antigen (HLA) molecules and elicit T-cell responses.
We adopt a highly personalized approach to screen for T-cell mediated recognition of mutated antigens as well as shared antigens using autologous antigen presenting cells that can process and present in all the potential HLA restriction elements.
Following this strategy, we aim to establish whether the presence of lymphocytes recognizing these antigens is associated with response. In parallel, we plan to advance personalized T-cell therapies to treat metastatic colorectal cancer, which is largely resistant to current anti-cancer strategies. We plan to file an IND to the Spanish Regulatory Agency in October 2020 that will enable us to treat patients with metastatic epithelial cancers with neoantigen-reactive TILs using this personalized approach. By enriching for neoantigen-reactive lymphocytes, we hope to enhance the efficacy of TIL therapy in epithelial cancers.
In summary, our group focuses on better understanding the naturally occurring T-cell response to cancer and establishing ways to exploit these antitumor responses to develop more effective, powerful, and precise immunotherapies against cancer.