MICA: Phase IIb randomised clinical trial repurposing ATRA as a stromal targeting agent in a novel drug combination for pancreatic cancer (STAR-PAC2).

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.

Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma) remains a lethal disease. Surgical excision offers the best chance for cure but only is feasible in less than a tenth of patients. Systematic reviews highlight the need for new treatment strategies. No effective neo-adjuvant protocols exist to enable surgical excision for PDAC. We propose a proof-of-concept clinical trial to test whether a combination of the state-of-the-art chemotherapy (gemcitabine & nab-Paclitaxel) and repurposing All Trans Retinoic Acid (ATRA) to target the stroma may extend progression-free survival and enable more successful surgical resection.

Desmoplastic stroma and hypo-vascularity impede successful delivery of chemotherapeutic drugs for PDAC. Pancreatic stellate cells (PSC) are critical for the desmoplastic stroma and mediate cancer cell pro-survival and pro-invasive capability through multiple signalling cascades. Quiescent PSC (normal pancreas) store retinol, which is lost in the activated state (PDAC). This effect is maximal when PSC constitute the predominant component of the cellular mix, as seen in surgical resection specimens. This multi-faceted tumour-stroma cross-talk is unlikely to be blocked effectively by targeting a single pathway. Dampening the tumour-promoting interaction between cancer and stromal cells or, in other words, normalising the desmoplastic stroma, by 'multi-targeting' agents may enhance traditional chemotherapy.

Our published preclinical work, and unpublished preliminary data from phase IB clinical trial demonstrate that we can safely deliver gemcitabine-nab-Paclitaxel-ATRA combination to patients with potential therapeutic benefit. In this proposal of a randomised controlled trial, we wish to assess if 'co-targeting' of both cancer and stromal compartments can potentially delay tumour progression over and above standard chemotherapy alone.

Pancreatic cancer is a disease with high unmet clinical need.

Currently, pancreatic cancer is the fourth-highest cancer killer worldwide (~310,000 patients), responsible for 6% of cancer deaths (overall median survival ~3 months). With an ageing population, the Pancreatic Cancer Action Network anticipates this age-related disease becoming the second leading cause of cancer death by 2020 (Rahib 2014).

The only curative procedure, surgical excision, is feasible in a minority of patients (~10% resectable pancreatic ductal adenocarcinoma, rPDAC, or borderline resectable, brPDAC). 35% of patients present with locally advanced (laPDAC) disease, involving major vessels, which precludes surgical excision. The remaining 55% diagnosed with metastatic disease (mPDAC) will benefit minimally from standard chemotherapy.

Thus this proposal which will prolong survival in laPDAC and increase the number of patients undergoing curative surgical resection is positioned correctly to benefit a large cohort of patients. Furthermore, exploratory objectives have potential to tailor therapy to sub-group of patients in an appropriate manner.