Clinical Trials Targeting the Stroma in Pancreatic Cancer: A Systematic Review and Meta-Analysis

Abstract

The tumor microenvironment plays an important role in the initiation and progression of pancreatic adenocarcinoma (PDAC). In this systematic review, we provide an overview of clinical trials with stroma-targeting agents. We systematically searched MEDLINE/PubMed and the EMBASE database, using the PRISMA guidelines, for eligible clinical trials. In total, 2330 records were screened, from which we have included 106 articles. A meta-analysis could be performed on 51 articles which describe the targeting of the vascular endothelial growth factor (VEGF) pathway, and three articles which describe the targeting of hyaluronic acid. Anti-VEGF therapies did not show an increase in median overall survival (OS) with combined hazard ratios (HRs) of 1.01 (95% confidence interval (CI) 0.90–1.13). Treatment with hyaluronidase PEGPH20 showed promising results, but, thus far, only in combination with gemcitabine and nab-paclitaxel in selected patients with hyaluronic acid (HA)high tumors: An increase in median progression free survival (PFS) of 2.9 months, as well as a HR of 0.51 (95% CI 0.26–1.00). In conclusion, we found that anti-angiogenic therapies did not show an increased benefit in median OS or PFS in contrast to promising results with anti-hyaluronic acid treatment in combination with gemcitabine and nab-paclitaxel. The PEGPH20 clinical trials used patient selection to determine eligibility based on tumor biology, which underlines the importance to personalize treatment for pancreatic cancer patients.

Diffusion Kurtosis Imaging—A Superior Approach to Assess Tumor–Stroma Ratio in Pancreatic Ductal Adenocarcinoma

“…In that, the desmoplastic extracellular matrix (ECM) appears to be a rather promising therapeutic target [ 15 ]. Different therapeutic approaches are discussed, which specifically target the tumor stroma rather than the tumor cells itself, and indirectly could contribute to increased sensitivity of tumor cells to chemotherapy [ 16 , 17 ]. New therapy options for PDAC are urgently needed.…”

“…In 2017, the first US Food and Drug Administration (FDA)-approved treatment targeting non-neoplastic cells, which are present in the tumor stroma, was introduced: The anti-programmed cell death protein 1 (PD-1) monoclonal antibody pembrolizumab was approved as second-line therapy for treatment of a small subgroup of PDAC patients with mismatch repair deficiency [ 22 ]. Other therapeutic approaches directly targeting the myo-fibroblastic cells or matrix components, such as the sonic hedgehog pathway, platelet-derived growth factor (PDGF)-receptor, or different proteases to deplete and modulate the architecture of desmoplastic stroma, or the depletion of hyaluronic acid to improve drug delivery revealed beneficial effects [ 17 ]. Although the results of a couple of experimental studies on stroma-depleting drugs in PDAC were disappointing, various other therapies targeting or modifying the stroma are currently being investigated [ 17 , 22 ].…”

“…Other therapeutic approaches directly targeting the myo-fibroblastic cells or matrix components, such as the sonic hedgehog pathway, platelet-derived growth factor (PDGF)-receptor, or different proteases to deplete and modulate the architecture of desmoplastic stroma, or the depletion of hyaluronic acid to improve drug delivery revealed beneficial effects [ 17 ]. Although the results of a couple of experimental studies on stroma-depleting drugs in PDAC were disappointing, various other therapies targeting or modifying the stroma are currently being investigated [ 17 , 22 ]. However, since the stroma content is highly variable in PDAC, presumably not all patients would benefit from stroma-targeting therapies to the same degree [ 17 ].…”

Pathogenesis and Treatment of Pancreatic Cancer Related Pain

“…Pancreatic cancer patients receive a number of invasive interventions as part of the cancer diagnosis and curative/palliative treatment approaches (1, 3), either as part of standard-of-care or as part of clinical trials. Novel therapeutic approaches or combination treatments are continuously evaluated pre-clinically and clinically in an effort to replace current treatment-induced toxicities (37,38,(44)(45)(46)(47)(48)(49)(50)(51). Although the pain inflicted by cancer surgery or diagnostic procedures can be intense, these pain symptoms are generally short-lived and can be easily addressed pharmacologically in most cases (32,52).…”

The next generation of venom‐based drugs

“…2 “Many animal venoms, including fish and snake venoms, contain the enzyme hyaluronidase,” Dr Jenner says. “Hyaluronidase breaks down the extracellular matrix, and can thereby act as a spreading factor that allows venom toxins to better penetrate the bodies of envenomated victims.” Incidentally, hyaluronidase may increase the penetration of chemotherapy to some malignancies, including certain pancreatic cancers 7 …”