Study Looks for Ways to Reduce Incidence of Tobacco-Associated Pancreatic Cancer

In an interview with Targeted Oncology, Nagaraj Nagathihalli, PhD, further explained the basis behind his study examining tobacco-associated pancreatic cancer and his plans to improve overall survival in this patient population.

The pancreatic cancer space as a whole is a major unmet need due to aggressive mutations, resistance to therapies, and discouraging survival rates. Further, over 25% of all pancreatic cancer cases can be traced back to tobacco use.

According to Nagaraj Nagathihalli, PhD, tobacco use is one of the most prevalent causes of severe malignancies, including pancreatic carcinomas, and one's risk of getting a diagnosis of cancer only increases with exposure.

In the United States, cases of pancreatic cancer are only increasing and there is a very high burden of this disease. Though pancreatic cancer is currently the 12th most commonly diagnosed cancer worldwide, and it is currently the third leading cause of cancer-related death in the United States after lung and colon and expected to become the second by 2030.1

“Over 25% of these cases will occur in lifetime tobacco users, making tobacco the single largest modifiable risk factor for the development of pancreatic cancer. Despite the significant association between smoking and pancreatic cancer, our understanding of the molecular underpinnings governing pancreatic cancer aggressiveness after extended tobacco use remains limited,” stated Nagathihalli, associate professor at Sylvester Comprehensive Cancer Center, part of the University of Miami Health System and the University of Miami Miller School of Medicine, in an interview with Targeted OncologyTM.

To address these issues faced by patients with pancreatic cancer, Nagathihalli aims to identify the various driving mechanisms linked with tobacco use in pancreatic cancer. This research will examine the progression and aggressiveness of pancreatic cancers associated with tobacco use with the hopes of developing new therapeutic strategies to reduce the poor outcomes associated with this disease.

In the interview with Targeted Oncology, Nagathihalli further explained the basis behind his study examining tobacco-associated pancreatic cancer and his plans to improve overall survival in this patient population.

Targeted Oncology: Can you discuss the basis of your plans for studying tobacco smoking-induced cancer?

Nagathihalli:Tobacco use has reached epidemic proportions worldwide and emerged as 1 of the most prevalent causes of several severe malignancies, including esophageal, oral, breast, colon, and pancreatic carcinomas. Carcinogenic compounds from tobacco are quickly absorbed into the bloodstream and cause pancreatic injury by a series of oncogenic events that culminate into tumor progression. The risk of cancer increases with exposure, and those who smoke 2 or more packs of cigarettes a day are 10 times more likely to develop pancreatic cancer during their lifetime.

Over 25% of all cases of pancreatic cancer can be linked to smoking or other tobacco use.

Despite such a high prevalence of tobacco-associated pancreatic cancer in the population, mechanistic understanding of how tobacco consumption precludes pancreatic neoplasia remains limited. Ingesting tobacco smoke triggers inflammatory and immune responses resulting in fibrosis of the pancreatic parenchyma, providing a milieu amenable to the aggressive progression of pancreatic neoplasia, and evading therapeutic intervention.Our previously published and ongoing seminal studies have established robust in vivo mouse models that can adequately recapitulate tobacco smoking-induced cancer in vivo.

What are the major factors contributing to pancreatic cancer aggressiveness, and your plans to address these issues?

Pancreatic cancer remains a major therapeutic challenge. Three main factors that contribute are aggressive advancement, resistance to therapy, and dismal survival rates in patients with pancreatic cancer. Firstly, activating KRAS mutations are present in over 90% of pancreatic tumors, which drives an inflammatory program that establishes immune exclusion in the pancreatic cancer tumor microenvironment, and subsequent additional loss of p53 progresses to aggressive, invasive, and metastatic pancreatic cancer.

Second, a hallmark of pancreatic cancer is the presence of a dense desmoplastic cellular milieu composed of stromal cells, including fibroblasts and immune cells, that support tumor progression and act as a barrier to drug delivery and anti-tumor immune activity. Third, even at early precancerous stages, inhibitory signals limit the recruitment, activation, and function of immune effectors within the tumor microenvironment to support cancer growth. Our proposed study explicitly addresses these barriers to improve therapeutic response and overall survival in tobacco-smoking models.

What are your plans to improve the overall survival of pancreatic cancer?

The studies in this proposal will advance therapeutic options and are designed explicitly for tobacco-associated cancers. Our previous efforts to understand the mechanism of pancreatic cancer progression have uncovered the critical role of activated cyclic AMP response element-binding protein 1 [CREB], a nuclear transcription factor that binds to the cAMP response element of the promoters of its target genes. Tobacco smoking aggravates tumor progression by activating CREB, which is correlated with a worse disease prognosis.

The exact contribution of CREB to smoking-induced pancreatic neoplasia is a poorly understood nexus. CREB can be considered an oncogene due to its role in upregulating the secretion of factors that imbue an immunosuppressive microenvironment. The complex interactions between various differently regulated cell types reflect the heterogeneous cellular contributions that lead to the progression of pancreatic cancer. Capitalizing on our preliminary data and unique experimental models we have created, including genetic mouse models, patient-derived xenografts, organoids, and primary cell lines, we seek to define the functional significance of cellular signaling pathways contribution to pancreatic tumorigenesis, unravel the complexity of heterogeneous smoking-induced pancreatic cellular dysplasia that propel tumorigenesis, and exploit these findings to develop improved strategies to develop novel treatment.

As CREB signaling is altered in a variety of other malignancies where tobacco smoking is a risk factor, our findings will provide a broader impact on many human cancers. Overall, the successful completion of these studies will determine whether a personalized approach for tobacco-associated cancers can advance progress toward cures and improve survival in pancreatic cancer patients.

What was the health impact on patients with pancreatic cancer, and what are your plans to study this disease?

The incidence of pancreatic cancer in the United States is rapidly increasing. Despite being the 12th most common cancer diagnosed, pancreatic cancer will soon overtake colorectal cancer as the second leading cause of cancer death in Florida. Over 25% of these cases will occur in lifetime tobacco users, making tobacco the single largest modifiable risk factor for the development of pancreatic cancer. Despite the significant association between smoking and pancreatic cancer, our understanding of the molecular underpinnings governing pancreatic cancer aggressiveness after extended tobacco use remains limited.

Although it has long been known that pancreatic cancer is an immunologically barren tumor, the mechanisms employed by pancreatic cancer to evade the body’s natural immune defenses remain poorly understood. Using clinical and laboratory data, we have discovered that CREB is indispensable for the development and progression of pancreatic neoplasia.

Our work revealed the critical role of CREB in promoting pancreatic inflammation, fibrosis, and immunosuppression through the recruitment of tumor-associated macrophages, inhibitory myeloid-derived suppressor cells, and regulatory T cells in genetic mouse models, which drives treatment resistance.

In concordance with these findings, we have found that targeting tumor-intrinsic CREB increases the sensitivity to chemotherapeutic agents in genetic mouse models. However, as CREB affects numerous downstream transcriptional networks, the precise mechanisms by which CREB promotes incipient neoplasia, treatment resistance, and immune suppression in pancreatic cancer remain entirely unexplored. Our data shows that tobacco use overwhelmingly activates CREB signaling, which fosters the immunosuppressive tumor microenvironment that is a hallmark of pancreatic cancer tumorigenesis and progression.

Confirming our hypothesis can elucidate a therapeutic target to enhance the success of existing cancer therapies for tobacco smokers with pancreatic cancer, directly impacting a massive population of Americans who currently suffer without treatment options. Importantly, our project can potentially improve the survival of smokers with pancreatic cancer.

How are you planning to advance your studies and develop a clinical implementation of these results?

Although every cancer is different, it is essential that the scientific community integrates the lessons we have learned from other tobacco-related cancers into therapeutic approaches.

We plan to test and target the pathways in experimental models that recapitulate tobacco smoking, pharmacologically identify new clinically important mechanistic targets, identify adjuvant therapeutic avenues to potentiate immunotherapy efficacy in pancreatic cancer, and study the translational potential for treatment using targeted therapy combined with immunotherapy.

Work from our group and others suggests that pancreatic cancer is characterized by the accumulation of a fibro-inflammatory stroma composed primarily of cancer-associated fibroblasts, myeloid-derived suppressor cells, and tumor-associated macrophages. However, many important mechanistic aspects of immune biology remain unexplored in pancreatic cancer. Both immune stimulation and curtailing immune evasion are crucial to improve outcomes for pancreatic cancer patients, who are uniquely susceptible due to their specific smoking-induced mechanism.

Due to the current paucity of knowledge regarding how tobacco affects the immune response to pancreatic cancer, our research has the potential to inform the identification and development of novel treatments and preventative strategies to eliminate the morbidity and mortality associated with tobacco-induced pancreatic cancer. In addition, we have strategically utilized existing clinically approved drugs in our experimental design. Although specific combination strategies have yet to be explored in treating pancreatic cancer, certain single agents are currently approved and well-tolerated for treating various other solid tissue malignancies. This experimental design has the potential for a near-immediate clinical implementation of positive results. We believe our studies will improve survival outcomes for tobacco-associated Floridians with pancreatic cancer by developing new combination-based therapies.

Is there any translational application of these studies in the future?

In addition to defining potential drug targets, the information generated from studies of pancreatic cancer malignancy can allow for the repurposing of many existing drugs for near-term clinical use. Interestingly, 30-40% of all FDA-approved drugs target GPCR pathways, many of which affect PKA-CREB signaling. Therefore, the knowledge developed from this study can be paradigm-changing because the outcomes of our research will help repurpose a CREB inhibitor for treating pancreatic and other cancers.

Reference:
Pancreatic cancer facts. Updated June 28, 2021. Published April 27, 2022. Accessed October 19, 2022. https://bit.ly/3eK357G