Translational Oncology

PIs: Antonio González and Beatriz Tavira

Ovarian cancer is one of the leading causes of death among women and the most lethal cause of death from gynecologic malignancy. Traditional management of ovarian cancer (cytoreductive surgery and platinum-based chemotherapy) allows for temporary disease control, but 70% of treated patients relapse within the first three years.

Maintenance therapy based on a new generation of poly (ADP-ribose) polymerase inhibitors (PARP inhibitors or PARPi) has prolonged the time during which the disease does not progress. However, this new approach is not yet sufficient to keep the condition under control. Therefore, new combinatorial strategies for treating recurrent ovarian cancer are currently being investigated, and immunotherapy is one of the most promising. 

Several ongoing clinical trials are studying the effect of immunotherapy based on PD-1/PD-L1 inhibition and PARPi as part of maintenance therapy. Some of these trials are being led by researchers at the Clínica Universidad de Navarra and represent an opportunity for improving patients and identifying biomarkers associated with response or resistance to these new treatments. Specifically, the Spanish Ovarian Cancer Research Group (GEICO) has launched the phase III clinical trial ANITA (Atezolizumab and Niraparib Treatment Association), led by Dr. Antonio González-Martín, clinical PI of the Translational Oncology group. This study, which collaborates with several gynecological cancer research groups in Europe through the ENGOT network, includes patients with ovarian cancer who have previously received platinum treatment and have relapsed more than six months after the last treatment. These patients receive a platinum-based regimen followed by a PARPi (Niraparib) and are randomized to receive a PD-L1 inhibitor (atezolizumab) for the duration of treatment. 

This study's main objective is to identify predictive biomarkers of response/resistance to these drugs (PARPi and anti-PD-L1) and to create response profiles. This, would allow early selection of each patient based on their biological characteristics (genetic and immunological) to which specific treatment would be assigned according to their probability of response, allowing personalized treatment to be obtained. This personalized medicine approach opens the door to the selection from the outset of those women who are likely to respond, avoiding the appearance of unnecessary side effects due to the inappropriate use of drugs, improving the quality of life of patients, and saving costs for the healthcare system.

On the other hand, another of the present lines focuses on the study of changes in the tumor microenvironment induced by neoadjuvant chemotherapy with or without anti-angiogenic drugs (bevacizumab) in patients with recurrent ovarian cancer (MINOVA study, GEICO 1205).

In both projects, biological material (tumor tissue, blood, serum, or plasma) will be used to identify biomarkers associated with predicting response or resistance by analyzing changes in the tumor microenvironment after administration of the therapies.

In parallel, animal models of ovarian cancer will also be used to gain a more detailed understanding of the complexity of the biological pathways involved in the origin and development of this disease, as well as the mechanisms of metastasis and action of resistance to the different treatments used in the management of the disease. In this aspect, one of the main avenues of current study focuses on the analysis of the effect on the tumor microenvironment and metabolism of the combination of caloric restriction drugs and current ovarian cancer management treatments such as PARPi and immunotherapy. 

General objectives:

• Identifying biomarkers associated with response/resistance to the combination of PARP inhibitors and immunotherapy by high-throughput analysis techniques (proteomics by mass spectrometry and multiple protein quantification by Luminex) in plasma. 
• Characterization of changes in the tumor microenvironment by multispectral immunophenotyping (Vectra Polaris) in patients with recurrent ovarian cancer after administration of different neoadjuvant therapies.
• Generation of preclinical models of ovarian cancer and their application for the study of therapies and models of resistance and metastasis.

PI: Rubén Pío

The efficacy of antitumor immunotherapy is limited by intrinsic genetic factors. Mutations in KRAS, STK11 or TP53 define distinct lung tumor subgroups with clear biological and therapeutic differences. Tumors with KRAS/STK11 mutations express lower levels of immune activation markers, including PD-L1, and show a higher number of neutrophils, possibly with immunosuppressive capacity. In contrast, tumors with KRAS/TP53 mutations show a higher mutational burden and denser T-cell and NK-cell infiltration. Consistent with these observations, clinical response rates differ significantly between tumors with STK11 or TP53 mutations. Therefore, new therapeutic strategies that reverse the resistance of tumors with an immunosuppressive environment, such as STK11 mutated tumors, are required. 

Objectives

• Generation of a repository of KRAS/STK11mut and KRAS/TP53mut human lung adenocarcinoma samples.
• Immunological characterization of KRAS/STK11mut and KRAS/TP53mut human lung adenocarcinomas.
• Generation and characterization of isogenic mouse models of KRAS/STK11mut and KRAS/P53mut lung adenocarcinomas
• Preclinical evaluation of novel IO combinations for KRAS/STK11mut lung adenocarcinomas

This multicenter project, which also involves the Vall d'Hebon Cancer Institute and the PeterMac Cancer Center, will provide new insights into the oncogenic immunoediting mechanisms that drive primary resistance to PD-1 axis agents and will enable the development of new therapeutic strategies to overcome this resistance.

PIs: Rubén Pío and Daniel Ajona

The efficacy of antitumor immunotherapy is limited both by factors intrinsic to the tumors and by the presence of an immunosuppressive tumor microenvironment. In addition, a significant number of patients suffer from adverse effects related to immunotherapy.

Our group has demonstrated, in preclinical models, that inhibition of the complement C5a/C5aR1 pathway reverses the resistance of non-small cell lung tumors (NSCLC) to PD-1/PD-L1 blockade. This finding has laid the groundwork for a clinical trial evaluating combined C5aR1 and PD-L1 inhibition in solid tumors (STELLAR-001; NCT03665129). Moreover, several groups have demonstrated that C5a/C5aR1 inhibition in mice attenuates colitis, one of the most frequent adverse effects of immunotherapy.

In the present project, we aim to exploit the potential of complement modulation, in particular of C5a/C5aR1, to reverse resistance to PD-1/PD-L1 blockade while attenuating its adverse effects. We also want to apply our recent discovery of the use of fasting as an enhancer of the effect of PD-1 blockade.

Objectives:

• Characterization of the function of complement proteins in the biology of cell subpopulations in the tumor microenvironment.
• Identification of complement-related traits and markers associated with immunotherapy resistance.
• Development of new drugs targeting the C5a/C5aR1 axis
• Evaluation of new immunotherapy combinations based on our findings.