Tumor Evasion and Novel Targets

IP: Juan Dubrot

Description: 

The immune system and its interactions with tumor cells are essential in cancer progression and treatment. Immunotherapy, particularly immune checkpoint blockade (ICB), has revolutionized cancer treatment in recent years.

Therapeutic blockade of negative regulators of T-cell effector functions, such as CTLA-4 or PD-1, has shown long-term responses in several different cancer types, including metastatic melanoma and lung cancer. However, compared to the results observed in patients with these malignancies, only a residual fraction of pancreatic cancer patients (approximately 2%) exhibited clinical benefit.

An intriguing strategy is the combination of immunotherapy with tumor irradiation. More than half of all cancer patients will receive a radiotherapy (RT) modality during their treatment. Originally, the rationale for its use was based on the ability of RT to kill cancer cells through the direct cytotoxic effects of ionizing radiation (IR). However, indisputable evidence recognized the important role of the host immune system in mediating and modulating the therapeutic effects of IR.

Following irradiation, inflammatory signals occur through activation of cell survival pathways and stimulation of the innate immune system, triggering cytokine production and immune cell recruitment. In addition, IR triggers immunogenic cell death of cancer cells that release tumor-associated antigens and damage-associated molecular patterns that induce activation of professional antigen-presenting cells, ultimately creating an immunostimulatory environment necessary for effective antitumor responses. On the other hand, growing preclinical evidence also indicates that IR induces resistance mechanisms, as evidenced by IR-induced PD-L1 upregulation in cancer and stromal cells and an increased influx of immunoinhibitory populations, such as regulatory T cells or myeloid suppressor cells.

These and other preclinical findings define the perfect scenario for strategies that can interfere with immunosuppressive mechanisms that restrict the anti-tumor effector functions of the immune system. Therefore, efforts to understand the mechanisms of action of this synergy in PDAC represent a great opportunity to address an unmet clinical need. However, although clinical trials are investigating the efficacy of radioimmunotherapy, there is a lack of clear understanding of how the combination works and the mechanisms of resistance that prevent better responses due, in some cases, to toxicities associated with the therapy. This results in large overspending on poorly designed trials and, more importantly, reduces the beneficial impact on many patients.

Using multidisciplinary approaches at different levels, we propose studying tumor changes after treatment to understand how radioimmunotherapy damages tumors and how tumors defend themselves. This will allow us to overcome resistance mechanisms in pancreatic cancer and discover new therapeutic targets.

Objectives:

• Characterize the molecular alterations radiotherapy produces in tumor cells and the tumor microenvironment.
• To discover new therapeutic targets that increase tumor sensitivity to radioimmunotherapy.

IP: Juan Dubrot

Description: 

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease that affects both women and men. Its high degree of resistance to virtually any type of therapy makes PDAC one of the greatest challenges in cancer. The development of new therapeutic strategies that improve the current clinical outcome in patients with this malignancy is critical. The only option for patients with advanced disease is an aggressive combination of chemotherapeutic agents such as gemcitabine or oxaliplatin, irinotecan, leucovorin and 5-fluorouracil (FOLFIRINOX) which are associated with severe toxicity.

In the present project we will study the reference chemotherapy in the treatment of PDAC (gemcitabine) in combination with PD-1 inhibitor antibodies. Immunotherapy and, in particular, immune checkpoint inhibitors (ICBs) have revolutionized cancer treatment in recent years and have shown long-term responses in several different cancer types. However, only a residual fraction of PDAC patients treated with immunotherapy show clinical benefit, making it crucial to combine them with other strategies.

Epigenetic modifications regulate gene expression and collaborate with genetic alterations to promote and control tumor progression by adapting genetic programs to the needs of the tumor under certain conditions. Importantly, epigenetic programs modulate the tumor microenvironment and can regulate antitumor responses that ultimately result in therapy failure.

Tumors possess multiple mechanisms to counteract a selective pressure caused by anticancer drugs or therapies. These mechanisms allow tumors to adapt to changing environments and meet the needs of the tumor. We will identify by using orthogonal approaches genes that are epigenetically modulated and are likely to mediate resistance to therapy. In addition, we are proposing the first CRISPR-based in vivo genetic screen to identify cancer cell intrinsic epigenetic mechanisms that hinder anti-tumor responses with chemo-immunotherapy in PDAC.

We will use the loss-of-function genetic approach to identify epigenetic regulators that limit in situ antitumor effector functions and thereby discover potentially novel targets that synergize with chemo-immunotherapy for the treatment of PDAC.

The proposed research will provide: i) mechanistic evidence of epigenetic programs causing resistance to therapy and ii) a solid basis for novel combinatorial strategies to enhance antitumor responses in PDAC patients.

Objectives:

• Multiomics characterization of epigenetic regulation in pancreatic cancer. 
• Identification of epigenetic mechanisms that contribute to therapy resistance in pancreatic cancer.