VHIO Presents 8 Research Proposals for Incoming ”la Caixa” Doctoral INPhINIT Fellowships
Ten early-stage researchers have the opportunity of starting a top scientific career @ VHIO, Severo Ochoa Centre, under ”laCaixa” Doctoral INPhINIT Incoming Fellowship programme, and boost their careers.
Decide which VHIO INPHINIT PhD Project fits better your research interests and APPLY through "la Caixa" application portal
In addition to financial support, the programme offers a 3-year employment contract and additional funding for conferences, courses, research stays, consumables, equipment, charges for the use of intellectual property, etc ; the fellowship includes a training programme in transversal skills such as entrepreneurship, technology transfer, intellectual property, leadership, creativity, communication, teamwork, personal development, planning, assertiveness and networking.
The final results will be published on the ”la Caixa” Foundation website on June 7, 2024.
More Information and Application:
Retaining ”la Caixa” Doctoral INPhINIT Fellowships
This frame is addressed to any discipline and any university or research center in Spain or Portugal. Candidates must have resided or carried out their main activity (work, studies, etc.) in Spain for more than 12 months in the 3 years immediately prior to the call deadline. All the VHIO labs are open to host candidates through the Retaining frame. APPLY HERE
Deadline for submitting applications February 15, 2024.
PROJECT DESCRIPTION
Dissecting the cellular basis of cancer immunotherapy through combinatorial genetics | Francisco Barriga, PhD
RESEARCH PROJECT
Our group develops and applies state of the art genetic approaches to answer outstanding questions in cancer biology. For this, the lab is developing two major research lines: first, the functional dissection of large-scale chromosomal changes known as copy number alterations (CNAs). Second, the development of next generation mouse models to dissect the in vivo biology of complex cell states that are currently intractable with standard approaches. We are particularly interested in cancer immune surveillance, tumor heterogeneity, and cancer genome evolution. Our long-term goal is to understand the complex biology of CNAs and their interaction with the immune system to identify new therapeutic strategies.
The project in the context of this fellowship is focused on identifying the CD8 T cell state responsible for the response to immune checkpoint blockade. For this, we have developed combinatorial genetics approaches that allow lineage tracing and ablation of distinct CD8 T cell states defined by concomitant expression of two genes. These novel mouse models will enable understanding the dynamics, plasticity, and contribution of distinct subsets of CD8 T cells to immune checkpoint blockade, the most used type of immune therapy in cancer. We will use these unique combinatorial models to measure the early and late responses to tumors, following cell state transitions via lineage tracing, immune phenotyping, single cell transcriptomics, and cellular ablation. We expect this project will give us an unprecedented level of insight into the cellular substrate of immunotherapy, which will help better stratify patients and develop therapeutic approaches to enhance response rates.
JOB POSITION DESCRIPTION
The applicant will join the Cancer Genome Engineering laboratory at VHIO. The CGE lab currently has 6 members: the group leader, a lab manager, a technician, a postdoc, and two PhD students. The lab is structured so that all team members directly learn and contribute to each other´s projects supervised by the group leader, and where each lab member contributes to their own research project. The CGE lab is part of VHIO, a research center with a strong focus on preclinical and clinal oncology, and where the working model includes close interactions with all key players from bench to bedside. VHIO also has a vibrant trainee community, where all students present their ongoing research to a broad audience, participate in training courses, and are encouraged to develop their careers beyond just experimental work. Indeed, this role entails the applicant to join a PhD program, undertake required classes, and attend training courses necessary for the development of their project within the framework of the CGE laboratory.
All lab members of the CGE lab are directly supervised by the Group Leader, which will ensure the project and trainee have the necessary mentoring, resources, and tools to develop their scientific career in oncology research. The lab is currently funded by institutional, national (Spanish Science Ministry grant, Ramon Y Cajal grant), and international (ERC Starting Grant, Edward P Evans Foundation Award) funds.
Unlocking the Secrets of Long-Term Cancer Survivors: A Machine Learning Approach to Uncover Immunogenomic Markers for exceptional treatment responses | Francisco Martínez-Jiménez, PhD
RESEARCH PROJECT
The cancer immunogenomics lab is a young, multidisciplinary, and international team integrated by researchers with diverse academic backgrounds, such as medicine, statistics, computer engineer and biotechnology. Our main research focus on understanding the genomic basis of tumorigenesis and its interplay with the immune system. Our approach relies on performing large-scale tumor genomic computational analyses matched with a comprehensive profiling of the tumor’s immune microenvironment to better understand the tumor immune system interaction. Our final goal is to leverage this knowledge to improve the clinical development of tailored immunotherapies.
Advancements in cancer care have significantly improved over the past decade, largely attributed to early detection improvements and the emergence of immunotherapy treatment regimens. While most of these treatment benefits patients with primary tumors, over 90% of patients with metastatic tumors continue to face the challenges posed by this devastating disease. Nevertheless, there exists a small subset of patients (1%-30%, depending on the cancer type and the specific treatment) with metastatic tumors who demonstrate enduring and robust responses to anti-cancer therapies.
This project is dedicated to characterizing the genomic, transcriptomic, and immune relevant tumor associated with exceptional responses to anti-cancer treatments across various cancer types. We will leverage state-of-the-art computational analytical and machine-learning techniques, applying them to several cohorts of cancer patients who have received treatment, and for whom treatment responses are available. The ultimate objective is to identify molecular features that can be screened to predict patients likely to achieve long-term responses. This endeavor may also pave the way for novel therapeutic approaches to manipulate immunogenomic factors present in non-responders, thereby enabling their transformation into long-term responders.
JOB POSITION DESCRIPTION
We are seeking an enthusiastic and highly motivated candidate who is genuinely passionate about conducting large-scale computational analyses with the final goal of improving the survival and quality of life for cancer patients. The ideal candidate should have a background in life sciences, mathematics, or computer-related fields. Although other backgrounds will be also considered. Knowledge in data science, machine learning, and/or cancer genomics would be positively valued.
In this role, the candidate will play a pivotal part in the execution of the project. They will be responsible for processing sequencing data, conducting the necessary computational analyses, and leading the development of machine learning models. Furthermore, this position offers the opportunity to present study findings at both national and international meetings.
Finally, as a part of VHIO, the candidate will be immersed in a highly translational international ecosystem that includes computational biologists, fundamental scientists, and translational and clinical researchers. Additionally, they will be enrolled in the VHIO academy program (https://vhio.net/the-vhio-academy/), designed to provide support and comprehensive training for the next generation of scientists.
Functional characterization of Fusobacterium nucleatum and its associated microbiota in colorectal cancer | Paolo Nuciforo, MD, PhD
RESEARCH PROJECT
Recent evidence has underscored the significance of the cancer-associated microbiome in the initiation and progression of colorectal cancer (CRC). Our previous research has established a connection between the persistence of Fusobacterium at the tumor site after neoadjuvant therapy and shorter progression-free survival and poorer prognosis in locally advanced rectal cancer (LARC). Subsequent molecular analyses unveiled the coexistence of Fusobacterium with other microbiota species in rectal cancer (Fusobacterium cluster), predicting post-treatment recurrence. In this context, our primary objective is to delve deeper into the functional implications of Fusobacterium and its associated microbiota in the development and progression of CRC. Initially, our research will undertake the isolation of bacterial species directly from human tumors, specifically from the Fusobacterium cluster. The successful isolation of these species will pave the way for a more detailed understanding of their individual characteristics and contributions. Subsequently, our efforts will shift towards the optimization and standardization of a comprehensive range of in vitro models, including classical 2D cell cultures and cutting-edge 3D models such as spheroids and organoids. These models will be essential to understand the complex interactions between Fusobacterium nucleatum, its associated microbiota and the tumor microenvironment in CRC. Upon the completion of the functional characterization, we will proceed to the development of a therapeutic screening platform. Our objective is to modulate the intestinal microbiota to create an anti-tumoral microenvironment, activate the immune response, enhance treatment efficacy, and consequently reduce the risk of recurrence. The therapeutic interventions we intend to explore as potential modulators of the intestinal microbiota include antibiotics, pre- and probiotics, specific metabolites of interest, and bacteriophages. This research constitutes a crucial stride in advancing our understanding of the microbiome’s contribution to the development of CRC and the refinement of therapeutic strategies.
JOB POSITION DESCRIPTION
We are looking for a highly motivated and talented PhD candidate with a clear dedication to research impacting patient care. The candidate will take an active role in the research project, designing, planning and performing the research in the Molecular Oncology Group under the supervision of the team leader Paolo Nuciforo. The candidate will work in a multidisciplinary team of oncologists, pathologists, molecular biologists, research nurses, epidemiologists, and bioinformaticians. Research project tasks will include (but not limited to) study data and sample acquisition, sample processing (DNA extraction for 16S RNA gene sequencing, aliquoting for storage, …), perform molecular tests (PCR, ISH, …), data analysis, interpretation and presentation both to internal and international meetings, maintain knowledge on research topic (through bibliography search). The applicant should be able to work independently, but also to be a team player and be willing to contribute to the team’s success. Excellent English writing and oral skills are required.
Targeting the cell cycle in cancer therapy: novel mechanisms and opportunities for WNT and MYC-driven tumors | Marcos Malumbres, PhD
RESEARCH PROJECT
Targeted therapies against cancer have been the subject of intense research in the last decades. One successful example is the approval of inhibitors of cyclin-dependent kinases (CDK)4 and CDK6 as first-line treatment of hormone-receptor positive, advanced breast cancer. Because of their reduced toxicity and significant efficacy, CDK4/6 inhibitors are considered raising stars among the new cancer targets. However, many aggressive tumors are resistant to inhibiting CDK4/6, sensitive patients quickly develop resistances, and alternative targets are urgently needed. In the last years, we have generated solid in vitro and in vivo data supporting the development of therapeutic strategies targeting novel CDK family members, including members of the CDK14 and CDK16 subfamilies, a poorly-studied group of CDKs. Our data indicate that these proteins are responsible for maintaining nuclear and genomic integrity in liver cancer cells, and therapeutic intervention against these CDKs is a promising strategy to reduce the growth of MYC-driven hepatocellular carcinoma, a deadly disease. We aim here to generate mechanistic insights into the biological role of the CDK14-18 subfamily using a combination of cellular studies, genetically-modified mouse models, CRISPR screens and single-cell studies, as well as patient-derived models in breast, ovarian and endometrial carcinoma. In addition, we aim to develop and implement first-in-class CDK16-18-targeted therapies as a novel strategy against aggressive WNT or MYC-overexpressing tumors.
JOB POSITION DESCRIPTION
The candidate will join a highly dynamic group composed of several researchers at the postdoctoral and predoctoral levels, as well as technicians supporting the different projects in the lab (see lab composition at https://malumbreslab.org/). The laboratory started in new facilities inaugurated in a new research floor at the Vall d’Hebron University Campus, surrounded by several lab with a common focus on cancer, as well as clinical teams at the Oncology service at the Vall d`Hebron Hospital. The laboratory is also externally associated with the IRB Barcelona (https://www.irbbarcelona.org/en) for use of specific services such as genomics, proteomics or advanced microscopy among others. The laboratory is funded by several national and internacional grants, as well as specific agreements with pharma companies. The research institute (https://vhio.net/) incorporates multiple initiatives aimed to improve the PhD experience including Thesis Advisory committees, agreement with major universities in the Barcelona area etc.
Investigating the Crossroads of Aging, Senescence, and Immunometabolism in Anti-Tumor Immune Response | Mate Maus, PhD
RESEARCH PROJECT
Immune function progressively declines with age, contributing to the increased incidence and aggressiveness of cancer with aging. Exploring the mechanisms of immune aging, both on a systemic level and within the tumor microenvironment, holds the potential to reveal innovative strategies for cancer immunotherapy.
Aging brings about substantial changes in both systemic and cellular metabolism, and there is growing evidence to suggest that these might interfere with micronutrient availability and with immunometabolism thereby driving the decline in anti-tumor immunity of the elderly.
A notable change associated with aging is the diminished availability of iron, a critical element for the proliferation and effector function of immune cells. The connection between age-related iron dyshomeostasis and the decline in anti-tumor immunity remains largely unexplored.
We possess extensive experience in studying immunometabolism and its role in immune function and inflammation (Vaeth* and Maus*, et al., Immunity, 2017). Recently, we have identified iron dyshomeostasis as a key driver of senescence-associated inflammation and age-related tissue remodeling (Maus et al., Nature Metabolism, 2023), both of which play pivotal roles in tumorigenesis. In this project, our goal is to bridge these fields and address fundamental questions regarding the impact of age, inflammation, and cancer-associated iron dyshomeostasis on the immune system’s ability to prevent and combat cancer. We aim to identify novel approaches for assessing and addressing immune aging, ultimately enhancing anti-tumor immunity in cancer patients.
JOB POSITION DESCRIPTION
We are seeking a prospective PhD student with a keen interest in immunometabolism and tumor immunology. While prior experience with cancer models, prior work with immune cells (especially T lymphocytes), and knowledge in the field of aging are highly valued, they are not essential for the application.
The successful candidate will be responsible for conducting experiments involving isolated T lymphocytes, working with mouse models of cancer, and analyzing human primary biopsies to investigate the role of age- and senescence-associated iron dyshomeostasis in the function of tumor-infiltrating T cells.
This project offers an opportunity to work with a diverse range of techniques, including genetic modification of T cells, T cell transfer models, metabolomics, flow cytometry, analysis of clinical data, bioinformatics, and single-cell transcriptomics. The successful candidate will collaborate closely with both basic scientists and clinicians.
The objective of this project is to advance our understanding of the biological mechanisms that connect aging to the decline in anti-tumor immunity. Additionally, the project aims to identify new markers that can enhance patient stratification in immunotherapy and develop innovative therapeutic tools in the field of immunotherapy.
Led by Mate Maus, VHIO’s Aging and Cancer Group was established in October 2022 and advances insights into the mechanisms of aging and its connections to cancer. Our group focuses on novel paradigms that can quantify and modulate the processes of cellular senescence, immunosenescence, and organismal aging, and evaluates each in the context of oncology and longevity. We are dedicated to accelerating discovery and developing new approaches to ultimately improve outcomes for cancer patients and increase the number of years spent in good health for all individuals.
Unlocking Tumor Immune Response with Deep Learning Integrating Multi-Omics and Medical Imaging | Raquel Pérez, MD, PhD
RESEARCH PROJECT
Improving response evaluation to cancer immunotherapy: Cancer immunotherapy with immune checkpoint inhibitors (ICI) has become the standard treatment for some cancer types and represents a promising therapeutic strategy for many others. However, while some patients achieve excellent responses to ICIs, others do not respond and may experience severe side effects. Also, some patients may show peculiar responses such as pseudoprogression and hyperprogression. Therefore, it is crucial to find biomarkers that help us predict and better evaluate ICI response.
Through medical imaging, we can non-invasively obtain a representation of the entire body, repeatedly over time. VHIO’s Radiomics Group has developed a model based on radiomics data (i.e., from the computational analysis of medical images) that captures a tumor phenotype with a high probability of responding to ICIs (Radiology, 2021, doi: 10.1148/radiol.2021200928).
The PhD candidate will conduct a project that integrates medical and histological images in patients receiving ICIs to enhance response prediction. We also aim to track changes of the image phenotypes of tumors through radiomics analysis to capture earlier and more accurately if a patient is benefiting from ICIs.
The research group: The Radiomics Group was established at VHIO in October 2017. Their efforts center on advancing precision imaging in personalized medicine, towards ultimately improving outcomes for cancer patients by applying mathematical methods to image processing and artificial intelligence in the biomedical field. The Radiomics Group participates in 12 on-going research projects funded by competitive grants (6 of them with Raquel Perez-Lopez as principal investigator, achieving >2.5M of external funding).
The group led by Dr. Perez-Lopez consists of a multidisciplinary team with expertise in complementary areas of biomedicine and computer science. The group currently is formed by 17 members: 1 PI, 2 post-doctoral researchers, 2 computer scientists, 5 pre-doctoral students, 5 master’s students, 1 fellow in clinical research and 1 data manager.
JOB POSITION DESCRIPTION
Artificial Intelligence (AI) has demonstrated its ability to extract valuable insights from complex data, including medical images, which are routinely obtained in clinical practice. The Radiomics Group has already developed a machine-learning model for direct response prediction (as published in Radiology 2021) and a deep-learning model for predicting PD-L1 expression from baseline CT images (currently under review). Although these initial results are promising, their clinical utility remains suboptimal. By harnessing larger, more representative datasets and employing advanced deep-learning techniques, we aim to create a more accurate tool for tumor characterization.
This PhD program will include several objectives that will allow the student to develop new skills under the mentorship and support of the VHIO multidisciplinary team including:
1. Enhance the response prediction tool for immunotherapy. The student will utilize state-of-the-art deep-learning models including CNNs (e.g., ResNet, VGG, GoogleNet) and Transformers.
2. In order to ensure the stakeholder reliability and applicability of the tool, the PhD candidate will employ various approaches of AI explainability.
3. Integration of CT and H&E Images: the candidate will use deep-learning models with different architectures combining anatomical and molecular image information to improve the prediction capacity of the model.
4. The tool will be included in a software application that include image analysis processes and biomarkers obtained in this project. The student will collaborate with the software developers in the Radiomics Group to achieve this aim.
Developing innovative therapies for cholangiocarcinoma: from bench to bedside and back again. | Teresa Macarulla, MD. PhD
RESEARCH PROJECT
Upper Gastrointestinal cancers, often referred to as upper GI cancers, are a significant concern for public health. Traditional treatments like surgery, chemotherapy, and radiotherapy frequently do not provide the best results for patients dealing with upper GI cancers, leading to a high risk of mortality. Our group is led by Dr. Teresa Macarulla (MD, PhD), an expert in pancreaticobiliary cancer and a medical oncologist. Our group works closely together, combining the expertise of clinical oncologists with the innovative approach of the preclinical and translational team led by Dr. Tian Tian (MD, PhD). Our goal is to pioneer new and effective ways to treat upper GI cancers and identify key factors that can predict patient outcomes. Central to our strategy is the combination of breakthroughs in biomarker research with cutting-edge studies on the effectiveness of drugs. This approach allows us to tailor treatment options specifically for patients with upper GI cancers. Our clinical team has played a crucial role in developing molecular therapies that target the abnormal signaling pathways in cancers like pancreatic, gastric, and bile duct cancers (cholangiocarcinoma). We have actively participated in multiple clinical trials (phases I-III) aimed at exploring innovative anti-cancer strategies for upper GI cancers. Notably, the molecules we have tested have received approval from both the U.S. Food and Drug Administration and the European Medicines Agency, providing hope for improved treatments. Moreover, our preclinical researchers are conducting in-depth investigations into the (epi)genetic features of these cancers using patient-derived models. This research holds promise for enhancing the diagnosis and treatment of gastric, pancreatic, and bile duct cancers, guiding us toward a brighter future in the care of upper GI cancers. In this project, we propose combining clinical and preclinical research to develop novel therapies for cholangiocarcinoma patients.
JOB POSITION DESCRIPTION
Ph.D. fellow will work on a project aiming to understand the diversity of cholangiocarcinoma (CCA) tumor microenvironment and design the next-generation therapeutic strategies. Cholangiocarcinoma (CCA) is the second-most common hepatobiliary malignancy (accounting for ~15% of all primary liver cancers) and remains incurable (5-year survival rate, 7–20%). CCA is a highly heterogeneous tumor, and its complex cellular composition could explain its resistance to treatment and poor prognosis. How do CCA cells relate to the immune microenvironment? Does this relationship contribute to the previously reported low success rate of CCA immunotherapy? These questions need to be urgently addressed. Somatic mutations are frequently found in CCA patients. However, the functional impacts of these mutations on the CCA tumor microenvironment are still unknown. In this project, we will use state-of-the-art multiplexing techniques and high-throughput multimodal sing-cell technologies to study the tumor microenvironment in CCA patient samples. Moreover, we will also perform functional studies using patient-derived in vivo and ex vivo models.
Development of new diagnostic and therapeutic strategies to identify and counteract CDK4/6i resistance in metastatic estrogen receptor-positive breast cancer by circulating tumor DNA analysis and the use of patient-derived models.. | Violeta Serra, PhD
RESEARCH PROJECT
Endocrine therapy (ET) has greatly improved treatment for hormone-dependent or ER+ breast cancer. The addition of CDK4/6 inhibitors to ET has shown significant progress in both progression-free survival (PFS) and overall survival (OS) for ER+ metastatic breast cancer. However, resistance to these inhibitors remains a challenge, particularly due to genetic mutations in the estrogen receptor gene and specific tumor profiles. Our preclinical data links resistance to CDK4/6 inhibitors with a basal-like gene profile and overexpression of p16 or cyclin D1 (Palafox et al, Nat Comm 2022). A clinical challenge when treating ER+ MBC is identifying biomarkers for patients who will not benefit from CDK4/6 inhibitors and designing a tailored therapeutic approach. Circulating tumor DNA (ctDNA) analysis is gaining interest as a minimally invasive way to track disease progression, especially in cases where obtaining a tumor biopsy is difficult. Our goal is to develop predictive biomarkers using ctDNA analysis and patient-derived models (PDX) to explore new treatment combinations to overcome drug resistance in ER+ breast cancers.
The Experimental Therapeutics Group led by Dr. Serra has a unique expertise of conducting hypothesis-based targeted therapy research in breast cancer. This group uses a multidisciplinary strategy by working with oncologists and bioinformaticians, among others, and develops novel approaches to better understand the mode of action of novel therapies as well as identify new response biomarkers. Dr. Serra’s lab is embedded in Vall d’Hebron Institute of Oncology (VHIO), which has long history of cutting-edge research in cancer therapy and guarantees access to multiple molecular, genetic, and biochemical technologies. Noteworthy, in VHIO there is an already established pipeline that allows to apply translational research to in-vivo and ex-vivo studies by using patient material from Vall d’Hebron Hospital. This lab is currently composed of a group leader, two associate researchers, a pathologist (part-time), five PhD students, two technicians and one research assistant.
JOB POSITION DESCRIPTION
This PhD opportunity focuses on identifying both established and novel mechanisms of resistance to CDK4/6 inhibitors in combination with endocrine therapy (CDK4/6i + ET). The aim is to demonstrate the effectiveness of emerging targeted agents, including innovative ER-targeting compounds and novel cell cycle inhibitors, for potential implementation in clinical settings. Concurrently, the position involves the analysis of circulating tumor DNA (ctDNA) to pinpoint robust biomarkers for CDK4/6i + ET response. The ultimate objective is to develop an efficient real-time diagnostic approach to guide appropriate subsequent therapeutic interventions in clinical practice.
The main tasks will include the development and construction of a cohort of patient-derived xenografts (PDXs) sourced from individuals with ER+ metastatic breast cancer undergoing treatment with CDK4/6i + ET. This will include establishing correlations between molecular responses and clinical outcomes, identify primary and acquired resistance mechanisms specific to these therapies and evaluating the efficacy of new therapeutic strategies tailored to this patient population. Finally, the position will also entail the comprehensive analysis and identification of novel biomarkers present in the ctDNA extracted from plasma samples of patients treated with CDK4/6i + ET.
Carrying out these tasks will require a broad literature research, enrolling to courses offered by the PhD program and attending lectures and webinars from renowned scientists in the field of oncology. VHIO supports continuing education including language courses and the Course in Training Research Staff Users of Animals for Experimentation, which is essential to work with mice. In addition, this job position will also demand high communication and writing skills to present the data in scientific seminars, workshops or conferences, and to establish solid collaborations both national and international, as well as to publish the data in high impact factor scientific journals.
