Next-generation therapies for pancreatic cancer

Abstract

Introduction: Pancreas ductal adenocarcinoma (PDAC) is a frequently lethal malignancy that poses unique therapeutic challenges. The current mainstay of therapy for metastatic PDAC (mPDAC) is cytotoxic chemotherapy. NALIRIFOX (liposomal irinotecan, fluorouracil, leucovorin, oxaliplatin) is an emerging standard of care in the metastatic setting. An evolving understanding of PDAC pathogenesis is driving a shift toward targeted therapy. Olaparib, a poly-ADP-ribose polymerase (PARP) inhibitor, has regulatory approval for maintenance therapy in BRCA-mutated mPDAC along with other targeted agents receiving disease-agnostic approvals including for PDAC with rare fusions and mismatch repair deficiency. Ongoing research continues to identify and evaluate an expanding array of targeted therapies for PDAC.

Areas covered: This review provides a brief overview of standard therapies for PDAC and an emphasis on current and emerging targeted therapies.

Expert opinion: There is notable potential for targeted therapies for KRAS-mutated PDAC with opportunity for meaningful benefit for a sizable portion of patients with this disease. Further, emerging approaches are focused on novel immune, tumor microenvironment, and synthetic lethality strategies.

Keywords: BRCA; KRAS; Poly-ADP ribose polymerase inhibitor; homologous recombination repair; immune checkpoint blockade; pancreatic adenocarcinoma; targeted therapy; tumor microenvironment.

Figure 1:

Outlines (1) the impact of poly-ADP-ribose polymerase (PARP) inhibition in cells with intact homologous recombination repair (HRR) versus homologous recombination repair deficiency (HRD) cells and (2) the impact of Wee1 protein inhibition following DNA damage. First, in the absence of PARP inhibition, DNA single stranded breaks (SSBs) are detected and repaired via base excision repair (BER). PARP inhibition impairs SSB repair and culminates in the formation of DNA double stranded breaks (DSBs). Cells with intact HRR repair DNA DSBs via HRR. However, HRD cells rely on error-prone non-homologous end joining (NHEJ) which further destabilizes DNA and results in synthetic lethality. Second, DNA damage is detected by Ataxia telangiectasia and Rad3-related protein (ATR), which signals through checkpoint kinase 1 (CHK1) to the Wee1 protein, which functions to halt the cell cycle at the G2/M checkpoint until DNA repair is performed. However, inhibition of Wee1 facilitates bypass of the G2/M checkpoint prior to DNA repair, inappropriately initiating mitosis and causing cellular death. Created with BioRender.com.

Figure 2:

Selected KRAS (Kirsten rat sarcoma virus)-targeted therapeutic modalities under investigation or with disease agnostic-approval pancreatic ductal adenocarcinoma (PDAC). Section 1 outlines therapies targeting KRAS and upstream (SHP, Src homology-2 domain-containing protein tyrosine phosphatase-2; SOS1, Son of Sevenless 1) and downstream (RAF, v raf murine sarcoma viral oncogene homologue B1; MEK, mitogen activated protein kinase kinase; ERK, extracellular signal-regulated kinase) signaling pathways. Section 2 outlines the mechanism of small interfering RNA in selectively silencing KRAS expression by inhibiting translation of KRAS mRNA into KRAS protein. Section 3 outlines the three primary vaccine modalities under investigation in KRAS-mutated PDAC: mRNA vaccines, peptides vaccines and dendritic cell vaccines (DCVs). Created with BioRender.com.

Figure 3:

Summary of selected current and future therapeutic targets located on the tumor cell in PDAC. Therapeutic targets under investigation or with disease-agnostic approval are colored orange while those with FDA approval for PDAC are colored green (PARP inhibitor – Olaparib, EGRF inhibitor – Erlotinib). Multiple target therapy modalities are under investigation KRAS (Kirsten rat sarcoma virus) including allele-specific and pan/all KRAS enzyme inhibitors, vaccines, and small interfering RNA, as are therapies targeting the upstream (SOS1, SHP2) and downstream (RAF/MEK/ERK) signaling proteins of KRAS. In PDAC cells with methylthioadenosine phosphorylase (MTAP) deficiency, the accumulation of methylthioadenosine (MTA) causes endogenous inhibition of protein arginine methyltransferases 5 (PRMT5), a protein central to histone and non-histone methylation. Targeted inhibition of PRMT5 in MTAP-deficient PDAC may induce synthetic lethality. Poly-ADP-ribose polymerase (PARP) inhibition also induces synthetic lethality through impaired detection and repair of single-stranded DNA. BRAF (v-raf murine sarcoma viral oncogene homolog B1); EGFR (epidermal growth factor receptor); ERK (extracellular signal-regulated kinase); MEK (mitogen-activated protein kinase kinase); Neuregulin 1 (NRG1); NTRK (neurotrophic tropomyosin kinase receptors); PRMT5 (protein arginine methyltransferases 5); RET (rearranged during transfection); SHP2 (Src homology-2 domain-containing protein tyrosine phosphatase-2); SOS1 (Son of Sevenless 1). Created with BioRender.com.