MICA: Early phase clinical trial repurposing ATRA as stromal targeting agent in a novel drug combination for pancreatic cancer (STAR-PAC)

Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma) is a lethal disease. At present, surgical removal of the affected pancreas offers the best chance for cure. However, this is possible in less than a fifth of patients.

Research and clinical trials have suggested that this disease required new treatment strategies. At present, in fact, there are no chemotherapy or radiotherapy treatments available which will shrink the tumour to enable surgical removal of pancreatic cancer in the patients not eligible for surgery upfront.

Based on our observations from treating patients as well as our laboratory research, this proposal is a proof-of-concept clinical trial to benefit those patients who cannot undergo surgery up front. We propsoe to combine state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel) to target cancer cells and repurposing All Trans Retinoic Acid (ATRA) to target the stroma.

Stroma is the scar tissue surrounding the cancer cells. Pancreatic cancer is charactereised by a particularly dense scar tissue such that it hampers successful delivery of chemotherapy drugs. A particular cell type: Pancreatic stellate cells ( or PSC) are critical for this desmoplastic stroma. In fact, our research has shown 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 strategy by sending many different signals to cancer cells and immune cells. We have demonstrated that we can change this PSC behaviour back to 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 have shown 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 tumour in more patients with pancreatic cancer then what is possibly currently.

This grant proposal is the first step to translate these encouraging laboratory results to a routine clinical practice. In this proposal we want to determine whether we can combine these drugs without increasing toxicity when given to patients with pancreatic cancer. We will increase the dose of drugs in a step wise manner to demonstrate that this combination can be administered without additional side-effects. If we can demonstrate this is feasible, then we also need to determine if this drug is reaching the required levels in blood stream as well as in pancreatic cancer to have the desired effect. Finally we need to be able to measure this effect. Hence in this early phase clinical trial, we will investigate that we can deliver treatment at appropriate dose without increasing side-effects as well as monitor the beneficial and harmful effects of the treatment.

In future, that is outside this current proposal, we will carry out comparison of this combination treatment with other state-of-the-art or established treatments for patients with pancreatic cancer who cannot undergo surgery upfront. Our goal will then be to develop an effective treatment given to patients before surgery, to increase the chances of surgical removal of cancer of the pancreas. Thus, translation proposal of of laboratory experiments into a clinical trial exploits the 'co-targeting' of both cancer and stromal compartments.

Pancreatic cancer (PDAC: pancreatic ductal adenocarcinoma) is a lethal disease. Surgical excision offers the best chance for cure but only is feasible in less than a fifth 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 enable surgical resection for locally advanced PDAC by developing a combination of the state-of-the-art chemotherapy (gemcitabine and nab-Paclitaxel) and repurposing All Trans Retinoic Acid to target the stroma.

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 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 preclinical data demonstrate that we can both target effectively and measure changes within, the stroma following targeting of PSC, using ATRA. Further data suggest other stromal compartments (immune cells and vasculature) also can 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). Thus, translation of preclinical data into clinical trial exploits the 'co-targeting' of both cancer and stromal compartments in a step-wise development.

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 (~20% 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 45% diagnosed with metastatic disease (mPDAC) will benefit minimally from standard chemotherapy.

Thus this proposal which will 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.