Reportedly, the PC stroma might comprise a considerable amount of HA, which is a high-molecule glycosaminoglycan comprising repeating units of D-glucuronic acid and N-acetyl-glucosamine[59,60]. Reportedly, HA levels in PC tissue might reach 12-fold higher than that found in healthy pancreatic tissue. In addition, PC cells typically express high levels of the primary HA receptor, CD44[62,63]. When HA binds to CD44, four major signaling pathways activated in PC cells are as follows: RAS, Rac, MAPK, and phosphatidylinositol-3-kinase. In fact, signaling through these pathways accelerates the proliferation, epithelial-to-mesenchymal transition, stemness, and metastatic capacity of PC cells and increases their resistance against chemotherapeutic drugs[64-70]. Besides its significant tumor-promoting effects, HA is a crucial contributor to the impaired blood perfusion of tumor cells, increased tumor hypoxia, and, more crucially, insufficient drug delivery to the tumor, as mentioned previously[1,60,69,70].
Some preclinical studies have reported that the enzymatic degradation of HA using PEGylated human recombinant hyaluronidase PH20 (PEGPH20) in genetically engineered mouse models of PC could prompt the re-expansion of collapsed tumor vessels and promote doxorubicin and gemcitabine delivery. Furthermore, the combined use of gemcitabine and PEGPH20 exhibited a synergistic effect and substantially inhibited the tumor growth, resulting in the upgraded survival of animals. Conversely, gemcitabine monotherapy only modestly affected the tumor growth compared with PEGPH20 alone. Provenzano et al reported similar findings and observed that PEGPH20 effectively ablated HA from metastatic deposits as with primary tumors and reinstated the vascular pattern.
Consequently, a phase 1b study by Hingorani et al evaluated the safety and efficacy of escalating doses of intravenous PEGPH20 combined with gemcitabine in patients with metastatic PC. The treatment was well tolerated by patients (n = 28) and exhibited a promising clinical activity. However, patients with tumors comprising higher HA levels seemingly benefited more from this treatment than those whose tumors had lower HA levels. In addition, the median progression-free and overall survival durations were 7.2 and 13 mo for patients with high HA levels and 3.5 and 5.7 mo for patients with low HA levels, respectively. Notably, these results encouraged further clinical research.
The final outcomes of phase 2 HALO-109-202 study, in which PEGPH20 was administered together with nab-paclitaxel plus gemcitabine regimen, were presented at the 2017 American Society of Clinical Oncology Annual Meeting. The study randomized 279 patients with untreated metastatic PC to receive either PEGPH20 plus chemotherapy (100 patients treated) or chemotherapy alone (160 patients treated). The combination therapy substantially improved the median progression-free survival (primary endpoint: 6.0 mo vs 5.3 mo; P = 0.045) in unselected patients. In HA-high patients (34% of enrolled patients), a significant increase was again noted in the progression-free survival with PEGPH20 plus chemotherapy compared with chemotherapy alone (median: 9.2 mo vs 5.2 mo; P = 0.48). However, no significant difference was observed between the two treatment arms regarding the overall survival (median: 11.5 mo vs 8.5 mo; HR, 0.96). Apparently, thromboembolic events pose a primary complication of PEGPH20 treatment. In the first stage of this phase 2 study, none of the patients randomized to PEGFP20 arm was provided thromboprophylaxis, and 43% of these developed thrombosis, causing a temporary cessation in the treatment. However, in the second stage, the rate of this complication was decreased to 28% with the administration of enoxaparin prophylaxis. PEGPH20 treatment was also associated with increased incidence and severity of other manageable side effects, such as painful muscle spasms, arthralgia, peripheral edema, and neutropenia. Overall, PEGPH20 is the first stroma-targeting agent that has demonstrated its efficacy in a clinical setting. Currently, a phase III study (HALO Pancreatic 301; NCT02715804) is recruiting patients with stage IV PC whose tumors have a high level of HA to validate phase II results.
In contrast, a recently presented randomized phase I/II study evaluating the efficacy of PEGPH20 and modified FOLFIRINOX in patients with metastatic PC who have a good performance status suggested that PEGPH20 can have a detrimental effect on OS (HR = 0.48). Therefore, further studies are needed to clarify whether the benefit from the use of PEGPH20 is restricted to patients treated with gemcitabine and nab-paclitaxel .
Secreted protein acidic and rich in cysteine
SPARC (also known as osteonectin or basement membrane protein 40) is a member of the matricellular proteins group and plays regulatory roles in cellular proliferation and adhesion. Guweidhi et al described that primary and metastatic lesions of PC expressed SPARC 31-fold more compared with normal pancreatic tissue. In addition, PC cells fail to produce SPARC because of aberrant hypermethylation in their SPARC gene. Thus, almost all SPARC in PC tissue is produced by PSCs[75-78]. Reportedly, SPARC can increase the migration ability and invasive properties of PC cells[78-80]. In addition, SPARC can stimulate the MMP production in neoplastic cells, thereby enhancing their metastatic potential[75,77,81,82]. Accordingly, patients with PC whose tumors contain elevated amounts of SPARC have been reported to have worse survival compared with those whose tumors contain lower SPARC levels following radical surgery or chemoradiotherapy[80,83-85].
Owing to its high affinity for albumin, stromal SPARC, perhaps, increases the intratumoral delivery and efficacy of the chemotherapeutic drug albumin-bound paclitaxel (nab-paclitaxel) in patients with PC. In their phase I/II study, Von Hoff et al examined the efficacy of escalating doses of nab-paclitaxel in combination with fixed doses gemcitabine in 67 patients with previously untreated metastatic PC. The treatment resulted in an overall response rate of 48%, and the median overall survival duration of 12.2 mo. In the study, the SPARC status was assessed in 36 patients, and patients whose tumors had high SPARC expression (n = 19) exhibited better overall survival than patients whose tumors displayed low SPARC expression (median: 17.8 mo vs 8.1 mo; P = 0.0431). In addition, the study established a significant correlation between the stromal SPARC level and the patients’ survival (P = 0.013). However, SPARC in tumor cells did not exert any effect on survival (P = 0.15). Besides, the authors assessed the treatment-related stromal changes and intratumoral penetration of the drugs in a patient-derived xenograft mouse model of PC and demonstrated that tumors resected from mice treated with gemcitabine alone demonstrated an extensive desmoplastic stroma. However, tumors in mice treated with nab-paclitaxel alone or in combination with gemcitabine exhibited the reduced stromal content, which was accompanied by dilated tumor blood vessels. Thus, the intratumoral concentration of gemcitabine was determined to be 2.8-fold higher in nab-paclitaxel plus gemcitabine-treated mice compared with mice receiving gemcitabine alone.
On the basis of these results, Von Hoff et al conducted a phase III study in which 861 patients with metastatic PC were randomly allotted to receive either nab-paclitaxel plus gemcitabine or gemcitabine alone. Their findings established the superiority of the combination regimen over gemcitabine monotherapy. In addition, patients receiving nab-paclitaxel plus gemcitabine exhibited longer median overall survival compared with those receiving gemcitabine alone (8.5 mo vs 6.7 mo; P < 0.001). Furthermore, they demonstrated a better response rate (23% vs 7%; P < 0.001). Hence, it could be speculated that the tumor SPARC level could be used as a predictive marker to determine patients with advanced PC most likely to benefit from nab-paclitaxel–based chemotherapy.