The HPV-positive tumors are not more curable based on increased epithelial sensitivity to cisplatin or radiation therapy. Instead, radiation and cisplatin induce an immune response to this antigenic cancer. The implications of these results may lead to novel therapies that enhance tumor eradication for HPV-positive cancers.
Patients with densely innervated tumors suffer with increased metastasis and decreased survival as compared to those with less innervated tumors. We hypothesize that in some tumors, nerves are acquired by a tumor-induced process, called axonogenesis. Here, we use PC12 cells as an in vitro neuronal model, human tumor samples and murine in vivo models to test this hypothesis. When appropriately stimulated, PC12 cells extend processes, called neurites. We show that patient tumors release vesicles, called exosomes, which induce PC12 neurite outgrowth. Using a cancer mouse model, we show that tumors compromised in exosome release are less innervated than controls. Moreover, in vivo pharmacological blockade of exosome release similarly attenuates tumor innervation. We characterize these nerves as sensory in nature and demonstrate that axonogenesis is potentiated by the exosome-packaged axonal guidance molecule, EphrinB1. These findings indicate that tumor released exosomes induce tumor innervation and exosomes containing EphrinB1 potentiate this activity.
Background: NIVO (anti-PD-1) is approved for the treatment of several cancers including advanced melanoma, but its efficacy in other types of skin cancer has not yet been evaluated. MCC is a rare and aggressive form of skin cancer, with most tumors being associated with the Merkel cell polyomavirus. MCCs frequently express PD-L1, and MCC-reactive T cells express PD-1. Methods: In CheckMate 358 (NCT02488759), patients (pts) with 5 types of advanced virus-associated cancers who had received ≤2 prior therapies, with an ECOG PS of 0-1, were eligible to receive NIVO 240 mg Q2W until progression or unacceptable toxicity. Key exclusion criteria were active brain metastases, autoimmune disease, hepatitis, and HIV infection. Primary endpoints included objective response rate (ORR by RECIST v1.1) and safety; secondary endpoints were duration of response, progression-free survival (PFS), and overall survival (OS). Twenty-five pts with MCC were treated with a median follow-up of 26 wks (range: 5-35). Results: Among 25 treated pts, median age was 66 yrs, 68% were male, and 60% were treatment-naive; 12 of 18 (67%) tested tumors were virus-positive. In 22 response-evaluable pts, ORR was 68% (table) with ongoing responses in 13 of 15 (87%) pts. Responses occurred in treatment-naive pts (71%), in pts with 1-2 prior systemic therapies (63%), and in both virus-positive and virus-negative tumors; 67% of responses occurred at ~8 weeks. At 3 months, PFS and OS rates were 82% and 92%, respectively. Treatment-related adverse events of any grade and grade 3/4 occurred in 68% and 20% of pts; 12% of pts had treatment-related AEs that led to NIVO discontinuation. Response to treatmentResponse-evaluable pts (N=22)Treatment-naive pts (n=14)Pts with 1-2 prior systemic therapies (n=8)Best overall response – n (%)Complete response3 (14)3 (21)0Partial response12 (55)7 (50)5 (63)Stable disease4 (18)3 (21)1 (13)Progressive disease3 (14)1 (7)2 (25)ORR – % (95% CI)68 (45–86)71 (42–92)63 (25–92)Time to response, months; median (range)2.0 (1.8–5.3)––Duration of response, months; median (range)Not reached (0.0–5.6)–– Conclusions: NIVO induces rapid and durable tumor regressions in the majority of treatment-naive and treatment-experienced pts with advanced MCC, with a manageable safety profile. Updated clinical response and biomarker data will be presented. Citation Format: Suzanne L. Topalian, Shailender Bhatia, Antoine Hollebecque, Ahmad Awada, Jan Paul De Boer, Ragini R. Kudchadkar, Anthony Goncalves, Jean-Pierre Delord, Uwe M. Martens, Jose Maria Lopez Picazo, Ana Oaknin, William C. Spanos, Raid Aljumaily, William H. Sharfman, Shangbang Rao, Ibrahima Soumaoro, Alexander Cao, Paul Nghiem, Dirk Schadendorf. Non-comparative, open-label, multiple cohort, phase 1/2 study to evaluate nivolumab (NIVO) in patients with virus-associated tumors (CheckMate 358): Efficacy and safety in Merkel cell carcinoma (MCC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT074. doi:10.1158/1538-7445.AM2017-CT074
The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Ras v12 , resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.Significant associative evidence supports a role for human papillomavirus type 16 (HPV16) in the carcinogenic progression of at least 25% of head and neck squamous cell cancer (HNSCC) cases (27, 38). In particular, the incidence of HNSCC of the tonsillar region is increasing (18,20,38). The epithelial surfaces surrounding the tonsil (oropharynx) are cancerous in a very high (60%) proportion of cases that are HPV positive, and these cases present with more metastatic and advanced disease states (34, 38) than HPV-negative cases. The incidence of HPV-related HNSCC is also increased in individuals with human immunodeficiency virus/AIDS disease (10). While the data presented in the following studies pertain to HPV-related HNSCC they may also be applicable to cases of HPV-related cervical cancer, which remains the second leading cause of cancer-related death in women. Therefore, understanding the viral mechanisms that lead to cancer will help meet a need for HPV-specific targeted therapy.One of the major HPV viral oncogenes that allow progression to cancer is HPV16 E6. E6 has many potential carcinogenic effects, including telomerase activation and p53 degradation (26, 35). However, an understood mechanism that potentiates malignant progression has been associated with a PDZ (PSD-95, Discs Large, ZO-1) binding motif (PDZBM), a specific amino acid sequence that mediates protein-protein interactions with corresponding PDZ domain-containing proteins. High-risk HPV virus types 16, 18, 31, and 33 possess this binding motif at the E6 C terminus. In addition to this correlative evidence of increased malignant potential in humans, mouse studies demonstrated that PDZBM is required for HPV-related malignancy (37).The studies described below explored the role of the E6 PDZBM in binding and inducing loss of a PDZ domain containing phosphatase PTPN13. PTPN13 is a member of the nonreceptor phosphatases and specifically falls into a cl...
To provide a manipulatable system to study the mechanism of human papillomavirus 16 (HPV16) E6related transformation of an epithelial cell type affected by HPV16 in humans. Design: Biochemical and physiological studies of mouse tonsil epithelial cells (MTECs) transformed with HPV16 oncogenes plus H-ras in vitro and in vivo.
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