Pancreatic cancer’s dense scar tissue physically blocks chemotherapy drugs from reaching tumours. Fewer than one in ten patients can have their tumour surgically removed—the only chance for cure—because the cancer has already spread or is too large. This trial tests whether adding a vitamin A derivative, all-trans retinoic acid (ATRA), to standard chemotherapy can soften that scar tissue. In the lab, ATRA switches pancreatic stellate cells—the cells that build the scar—back to a dormant state, which starves the tumour of survival signals and makes it shrink. A phase Ib trial already showed the combination is safe. This phase IIb trial will measure whether it shrinks tumours enough to allow surgery in patients who currently cannot have it. If successful, the approach could turn an inoperable cancer into an operable one, repurposing an existing drug to change the physical environment around the tumour rather than attacking the cancer cells alone.
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Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma) is a lethal disease. Currently, surgical removal of the affected pancreas offers the best chance for cure. However, this is possible in less than one-tenth of patients. Research and clinical trials indicate that this disease requires new treatment strategies. At present, there are no chemotherapy or radiotherapy treatments available for patients not eligible for upfront surgery which will shrink the tumour; thus, enabling subsequent surgical removal of the pancreatic cancer. Based on our preliminary observations from treating patients in Phase Ib clinical trial (STARPAC) as well as our laboratory research, this proposal is a proof-of-concept clinical trial to benefit those patients who cannot undergo initial surgery. We propose to combine state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel) to target cancer cells and investigate repurposing of All Trans Retinoic Acid (ATRA) to target the stroma. Stroma is the scar tissue surrounding the cancer cells. Pancreatic cancer is characterised by a particularly dense scar tissue (termed desmoplasia) which hampers successful delivery of chemotherapy drugs. A particular cell type, the Pancreatic stellate cells (or PSC), is critical for this desmoplastic stroma. In fact, we have shown experimentally that PSC enable cancer cells to survive longer and spread faster. Cancer cells activate PSC from their dormant state. These activated PSC, in turn, engineer a pro-cancer response by sending many different signals to cancer cells and immune cells. We have demonstrated that we can change this PSC behaviour back to the dormant or quiescent state. Quiescent PSC (normal pancreas) store retinol or vitamin A which is lost in activated state (pancreatic cancer). Pancreatic cancer patients are deficient in Vitamin A. Thus they cannot revert to the normal PSC behaviour without medications to alter their behaviour. Our laboratory experiments show that we can both target effectively and measure changes within, the stroma following targeting of PSC, using ATRA. Moreover we demonstrate that other cells (immune cells and blood vessels) also can also be targeted, to the detriment of tumour behaviour, using ATRA. ATRA's effect is potentiated to reduce tumour size in combination with state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel). If we can substantially reduce tumour size, we can enable surgical removal of the tumour in more patients with pancreatic cancer then what is possible currently. We already have demonstrated in the on-going Phase Ib clinical trial that it is safe to combine these agents without increasing toxicity when given to patients with pancreatic cancer. This grant proposal is the next step in efforts to translate the encouraging laboratory and clinical results to a routine clinical practice. Now we will estimate the efficacy of this drug combination to prolong survival and shrink tumours of pancreatic cancer patients. Beyond this proposal, our goal will then be to develop an effective treatment to be given to patients before surgery, to increase the chances of surgical removal of cancer of the pancreas. Thus, this translational proposal of laboratory experiments into a clinical trial exploits the 'co-targeting' of both cancer and stromal compartments and involves repurposing existing agents based on clinical observations and sound biological experiments.
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