Pratibha Malhotra, Ranjith Palanisamy, Marco Falasca

Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6102, Australia

Pancreatic ductal adenocarcinoma (PDAC), the most commonly reported form of pancreatic cancer, is a lethal malignancy that contributes to the global cancer burden with high morbidity and mortality [1] . It has a poor 5-year survival mainly because PDAC poses a significant diagnostic challenge, has a high metastatic rate at diagnosis and is stubbornly resistant to therapy [2] .

The treatment options for PDAC are limited and depend upon the stage at which it is diagnosed [1] . At present, surgery remains the only realistic and potentially curative therapy. However,it is only available to about 15%-20% of the patients presenting resectable PDAC. Once metastasised, PDAC patients have a very poor prognosis. Based on tumor characteristics, chemotherapeutic drugs,alone or in combination, form the mainstay of therapy for metastasised PDAC. However, these strategies and the new upcoming anticancer drugs are unable to generate desirable results due to multidimensional bottlenecks ranging from intense desmoplastic reaction, immunosuppressive tumor microenvironment (TME) and drug resistance.

There has been an increasing interest in pancreatic cancer over the last decade, leading to better knowledge of its tumor biology,genetic and molecular characteristics, and factors contributing to resistance [3] . In a recent study, Bai et al. [4] reviewed the progress of comprehensive therapeutic strategies in advanced PDAC. In that study, the authors focused on diverse options encompassing conventional chemotherapy, targeted and immune system-based therapies, strategies for targeting elements of the TME and metabolism for battling this aggressive malignancy.

The advent of genome sequencing technologies and the knowledge that can be obtained from the Cancer Genome Atlas have empowered researchers to study genetic mutations and molecular pathways involved in PDAC, opening avenues for targeted therapy. The central idea behind targeted therapy is to selectively attack cancer cells and, consequently, the main objective is to identify specific tumor targets and responsive subgroups of patients.In PDAC, the 4 main genetic mutations (KRAS,TP53,CDKN2AandSMAD4) and pleiotropic signalling pathways provide grounds for consideration. TargetingKRASmutations and their downstream pathways is an attractive treatment option for PDAC patients due to their higher prevalence and their role in initiating cancerous genetic events [5] . Researchers are also targeting other mutations in PDAC includingHER2,STK11,BRCA1/2,ATM,ALKamplification,andNTRKandNRG1gene fusions. For some of the enlisted mutations, clinical trials are underway to probe the therapeutic potential and overall survival outcomes in patients [6] . Therefore, these studies provide grounds for identifying genetic mutations in PDAC patients to develop novel therapeutic strategies. Molecular profiling has also helped in understanding that malfunctions in DNA repair pathways can increase the risk of PDAC incidence. Therapies are available, with platinum-based chemotherapy for mutations occurring in homologous recombination genes such asBRCA1/2,PALB2used during double-strand DNA breaks and poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors for PARP enzymes involved in repairing single-strand breaks through base excision repair pathway. These drugs were commonly used as adjuvant therapies to achieve better response in patients [ 7 , 8 ].

In addition to defining genomic landscapes, next-generation sequencing (NGS) techniques are also helping in stratifying PDACs at transcriptomic levels as various molecular subtypes. Classifying PDACs as transcriptomic subtypes helps to reduce the various biases suffered while histopathologically defining a PDAC, as well as in swiftly understanding the characteristics and chemotherapeutic susceptibility of the tumor type. Thus, subtyping diagnosed PDAC patients may foresee the prognosis and offer the opportunity for personalized treatment options [9-11] .

Epigenetic modifications, in addition to genetic mutations, play a part in PDAC carcinogenesis and tumor aggressiveness. Hence,another field to explore is the potential of epi-drugs in PDAC. DNA methyltransferase 1 (DNMT) and histone deacetylase (HDAC) were approved by the European Medicines Agency (EMA) and the Food and Drug Administration (FDA) for some haematological cancers promoting research in solid tumors [12] . Bai et al. [4] , in their review, presented an overview of promising epigenetics-based therapies. Despite preliminary successes, first and second-generation epi-drugs have low efficacy and associated side effects [13] . Interestingly, Bai et al. also reviewed some natural compounds, such as curcumin and garcinol, that could alter miRNA expression in pancreatic cancer cells. However, additional studies are needed to map the epigenetic landscape of PDAC patients in more detail to understand its role in cancer progression and explore therapeutic options.

PDAC exhibits heterogeneity and a unique TME [14] . The TME encompasses stromal cells, epithelial cells, cancer-associated fibroblasts, and several immune cells that orchestrate the development of a desmoplastic and immunosuppressive microenvironment through different mechanisms [15] . Immunotherapeutic strategies for PDAC patients include strengthening anticancer responses, targeting immunosuppressed cells and reversing immunosuppressive mechanisms using monoclonal antibodies, vaccines, TME and immunomodulators as well as cell therapies. The dense fibrotic stromal microenvironment of PDAC provides a conducive environment for cancer growth and is acknowledged as an immune microenvironment regulator, contributing to chemoresistance. As a result,targeting different extracellular matrix components, along with chemotherapy and immunotherapy, is also currently under investigation. Therapeutic options to target other TME components, such as cancer stem cells and cancer-associated fibroblasts, are also being investigated at different levels [16] .

PDAC can rely on metabolic remodelling to adapt to host environmental stresses, consequently suggesting potentially new treatment targets for patients. The abnormal metabolic profile is known to remodel TME and contribute to poor prognosis [17] . Furthermore, oncogenic mutations lead to cell proliferation which in turn increases tumor metabolism. This might explain why autophagy is critical in sustaining growth and survival inKRASmutated tumors.Disrupting KRAS signalling has been shown to inhibit autophagy in pancreatic cancer [18] . In their review, Bai et al. briefly discussed the current strategies for targeting metabolism and autophagy inhibition.

PDAC is classified among the obdurate cancers, as the desmoplastic tumors are surrounded by an hypoperfused and low vascular vessel structure restricting therapeutic transport, subsequently reducing therapy effectiveness and promoting carcinogenesis. Several studies have shown that the immune checkpoint blockade therapy on PDAC patients had the lowest objective response rate compared to other tumor types. The physical barrier made by the desmoplastic reaction within PDAC stroma decreases T-cell infiltration thereby reducing the efficacy of immunotherapy [19] . To improve therapeutic efficacy, combination therapies for PDAC targeting distinct barriers are being intensively investigated. Studies have trialled approaches including combining chemotherapeutic drugs with tumor vaccines, antibody therapy with agonists and combining different chemotherapies. Ideally, the combination therapy will differ based on several factors such as genetic mutations, signalling pathways, chemotherapeutic drugs in use, resistance, and theranostic biomarkers. Furthermore, the drug delivery system, toxicity and dose pose a key challenge for developing combination therapies [20] . Novel research approaches, such as patient-derived xenograft and organoid culture system, will help in understanding cancer genetics and providing personalized drug screening and development [ 21 , 22 ].

Despite extensive research and new targeting approaches, the achieved results remain frustrating, as there is only a modest improvement in patient survival. Studies are continually focusing on improving existing strategies ranging from surgery to PDAC management. Furthermore, scientists are exploring other therapeutic options such as natural compounds alone or in combination with chemotherapeutic agents. Notably, an early diagnosis may affect PDAC outcomes. Investigations are currently underway to identify novel diagnostic and prognostic markers that would help improve clinical outcomes.

In conclusion, although many challenges remain unsolved,the upcoming technologies and extensive research in different sectors are shifting from conventional diagnosis, treatment and management methods to a more personalized approach aimed to improve both overall patients’ survival and quality of life.

Ackowledgements

Marco Falasca acknowledges the infrastructure and staff support provided by CHIRI, Curtin Medical School, Faculty of Health Sciences, Curtin University.

CRediT authorship contribution statement

Pratibha Malhotra : Conceptualisation, Writing - original draft.Ranjith Palanisamy : Writing - review and editing. Marco Falasca :Conceptualization, Supervision, Data curation, Investigation, Funding acquisition, Writing - review & editing.

Funding

This study was supported by a grant from the Australian Pancreatic Cancer Foundation and Keith and Ann Vaughan Pancreatic Cancer Fund.

Ethical approval

Not needed.

Competing interest

No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.