Therapeutic Innovation in Lung Cancer

PI: Karmele Valencia

Despite impressive progress in therapeutic strategies for non-small cell lung cancer (NSCLC), there are still many patients who cannot benefit from current therapies (chemo, radio, targeted therapy or immunotherapy).

We propose to identify new potentially druggable molecular alterations and evaluate mechanisms to break resistance to standard clinical treatments. Recently, we have published that DSTYK is altered in lung cancer and is associated with poor clinical prognosis. Furthermore, DSTYK controls cellular processes encompassing cytoprotective autophagy and mitochondrial welfare, and its inhibition sensitizes tumor cells to T cell-mediated death (Valencia et al. JEM, 2022).  

Objectives:

In the present project we will characterize DSTYK as a novel biomarker and therapeutic target to sensitize lung cancer to standard treatments. In parallel, we will elucidate the intrinsic and extrinsic mechanisms related to DSTYK in lung cancer progression and, finally, we will identify selective DSTYK inhibitors with significant and specific antitumor activity at the cellular level to subsequently propose drugs that can be immediately taken to the preclinical phase. Our ultimate goal, if our hypothesis is confirmed, is to develop, in collaboration with our Medicinal Chemistry Department, a specific drug to inhibit DSTYK activity to treat lung cancer and potentially other cancer patients.

PI: Karmele Valencia, Álvaro Teijeira, Jon Zugazagoitia, Pilar Martín, José Martínez, Aránzazu González.

Lung cancer patients face a 12-fold increased risk of developing fatal heart disease compared to the general population, especially in the first year after diagnosis. Therefore, early detection, monitoring and cardioprotective treatments are critical. Two out of three lung cancer patients are diagnosed at advanced stages, in which immunotherapy, specifically with immune checkpoint inhibitors (ICIs), has become the standard treatment. However, ICIs carry the risk of immunological adverse effects, such as myocarditis, heart failure (HF), atherosclerosis and thrombosis, reinforcing the significant role of inflammation in cardiovascular damage associated with anti-tumor therapy. 

Objectives:

The InCaRe consortium, composed of leading groups in lung cancer, cardiomyopathies and immunology, will lay the groundwork for the development of tools aimed at identifying patients with a high-risk immunological and cardiovascular profile prior to treatment. In addition, we will explore a comprehensive panel of molecular biomarkers capable of detecting early alterations induced by ICIs, linking them to disease progression and the possibility of predicting severe cardiovascular events. 

The ultimate goal is to comprehensively assess cardiovascular damage in experimental models and lung cancer patients, identify molecular biomarkers of early cardiovascular damage, and explore potential anti-inflammatory therapies to mitigate the cardiotoxicity of immunotherapy. InCaRe will provide valuable insights into immune response and autoimmune activity in lung cancer patients receiving immunotherapy.

PI: Karmele Valencia Marta Montes, Oskar Marín, Patricia Altea-Manzano.

Lung cancer remains the leading cause of cancer-related mortality worldwide. Patients with lung cancer rapidly develop chemoresistance, leading to disease progression. Treatments, such as platinum-based chemotherapy and taxanes, stop cell proliferation in a small population of cells. This process, known as therapy-induced senescence (TIS), is considered a cellular escape strategy from the direct cytotoxic effects of treatment. We have found that prolonged treatment with platinum-based doublet chemotherapy increases senescent cells in non-small cell lung cancer (NSCLC) models both in vitro and in vivo, which correlates with increased resistance to therapy. 

We hypothesize that there are specific mechanisms of therapy resistance associated with the presence of TIS cells, and that targeting senescence-induced mechanisms improves treatment response.  

Objectives:

We will investigate how senescent cells influence surrounding cancer cells and non-malignant cells, increasing their aggressiveness, resistance to therapy and ultimately leading to tumor relapse.
Specifically, we will: (1) evaluate the impact of TIS on the tumor microenvironment, (2) characterize TIS in lung tumors and identify its escape mechanisms in the face of therapeutic pressure, and (3) evaluate new drug combinations to prevent the activation of senescence-related mechanisms. 

With this project, we aim to elucidate the vulnerabilities of NSCLC tumors to define targets that modify TIS and propose new combination therapies to overcome resistance to chemotherapy.