Targeting tumor hypoxia to increase efficiency of multimodal and immunological therapeutic strategies in pancreatic cancer
Swiss partners
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Universitätsspital Zürich: Perparim Limani (main applicant)
Partners in the MENA region
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Gulf Medical University, Emirats Arabes Unis: Raefa Abou Khouzam (main applicant), Salem Chouaib, Rania Faouzi Zaarour, Ayesha Rifath, Nagwa Zeinelabdin, Husam Nawafleh
Other partners
- Gustave Roussy Cancer Campus, France: Jerome Thiery, Stéphanie Buart
- Mayo Clinic Jacksonville, Etats-Unis: Michael B Wallace
- Université de Strasbourg, France: Jean-Marie Lehn
Presentation of the project
Pancreatic cancer and pancreatic ductal adenocarcinoma (PDAC), in particular, is a disease of poor survival with less than 20% of patients amenable to the only potentially curative option that is surgery. Novel therapeutic strategies are required to improve patient outcomes. Immune checkpoint inhibitors (ICIs) that relieve the breaks on the immune response enabling the elimination of tumor cells, have revolutionized cancer care, but not in patients with PDAC, in which a maximum of 5% response rate was achieved in metastatic disease.
One underlying cause for the resistance to ICIs is the highly hypoxic and desmoplastic microenvironment of pancreatic tumors. We have shown through a hypoxia gene signature that PDAC patients with more hypoxic tumors experience worse survival and have a more immunosuppressed tumor microenvironment (TME) than those with less hypoxic tumors. Indeed, hypoxia is known to unleash a torrential response within the TME, activating pathways that enable tumor cell survival, immunosuppression, invasion, and metastasis, all of which contribute to disease malignancy. Furthermore, in hypoxic conditions, pro-angiogenic factors are expressed to produce blood vessels that can counter oxygen deprivation. However, the result is pathological angiogenesis with leaky and abnormal vasculature that fails to restore oxygen, but rather works to exacerbate hypoxia, immune exclusion, and suppression, as well as tumor progression.
Myo-inositol-trispyrophosphate (ITPP) is the first-of-its-class nontoxic agent that enhances oxygen release in hypoxia and synergizes with cytotoxic anti-cancer agents in preclinical-tumor models. There is a paucity of data describing the mechanism of action of ITPP in PDAC, and whether it exerts its anti-tumorigenic function through vasculature normalization in the context of this disease is unkown. In addition, despite the encouraging data supporting ITPP’s role in enhancing response to therapy, it is yet to be tested in combination with ICI. In addition, the efficacy of ITPP in PDAC tumor xenografts established in zebrafish larvae has never been investigated. This is highly relevant given that transparent zebrafish larvae which share 70% of their genome with humans and express more than 80% of cancer-associated genes, can provide real-time visualization of the drug’s mechanism of action at single cell resolution.
In this work the objectives are to validate our hypoxia gene signature, to evaluate for the first time a combination therapy of the oxygen enhancer ITPP and ICIs in pancreatic cancer mouse models and to determine ITPP’s efficacy in PDAC cell lines and patient-derived xenografts using zebrafish. Severing the feed-forward loop between hypoxia and angiogenesis in the TME through vascular normalization could be key to halting tumor progression and enabling anti-tumor immune cells to infiltrate the tumor mass, thus enhancing response to ICIs, and improving pancreatic cancer patients’ prognosis.
Thus far we have established zebrafish xenografts using two different human PDAC cancer cell lines and set up the treatment protocol with ITPP in this model. We show for the first time the applicability of ITPP in PDAC-derived zebrafish xenografts. Preliminary findings indicate that ITPP acts as an inhibitor of cell division in the TME of tumor xenografts. We have further found it to induce apoptotic cell death of one of the PDAC cell lines in vivo. Regarding vascular normalization, we have preliminary evidence of increased vascular function within the tumor-related vessels of ITPP-treated PDAC xenografts compared to controls.
With respect to the evaluation of ITPP on immune cell infiltration and its efficacy in combination with ICI, we have secured the pending ethical approval to proceed with this objective. Since then, we have determined the treatment dose of ITPP in one mouse model and will be proceeding to generate the mouse PDAC syngeneic tumors, and treating with ITPP alone, and in combination with an ICI.
Article in Seminars in Cancer Biology (2023)