Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients.

BackgroundGender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.MethodsForty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.ResultsOur murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.ConclusionsAlthough our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance

Novel Dedifferentiated Liposarcoma Xenograft Models Reveal PTEN Down-Regulation as a Malignant Signature and Response to PI3K Pathway Inhibition

Liposarcoma is a type of soft tissue sarcoma that exhibits poor survival and a high recurrence rate. Treatment is generally limited to surgery and radiation, which emphasizes the need for better understanding of this disease. Because very few in vivo and in vitro models can reproducibly recapitulate the human disease, we generated several xenograft models from surgically resected human dedifferentiated liposarcoma. All xenografts recapitulated morphological and gene expression characteristics of the patient tumors after continuous in vivo passages. Importantly, xenograftability was directly correlated with disease-specific survival of liposarcoma patients. Thus, the ability for the tumor of a patient to engraft may help identify those patients who will benefit from more aggressive treatment regimens. Gene expression analyses highlighted the association between xenograftability and a unique gene expression signature, including down-regulated PTEN tumor-suppressor gene expression and a progenitor-like phenotype. When treated with the PI3K/AKT/mTOR pathway inhibitor rapamycin alone or in combination with the multikinase inhibitor sorafenib, all xenografts responded with increased lipid content and a more differentiated gene expression profile. These human xenograft models may facilitate liposarcoma research and accelerate the generation of readily translatable preclinical data that could ultimately influence patient care

Efficacy of Tumor-Targeting Salmonella A1-R on a Melanoma Patient-Derived Orthotopic Xenograft (PDOX) Nude-Mouse Model

Tumor-targeting Salmonella enterica serovar Typhimurium A1-R (Salmonella A1-R) had strong efficacy on a melanoma patient-derived orthotopic xenograft (PDOX) nude-mouse model. GFP-expressing Salmonella A1-R highly and selectively colonized the PDOX melanoma and significantly suppressed tumor growth (p = 0. 021). The combination of Salmonella A1-R and cisplatinum (CDDP), both at low-dose, also significantly suppressed the growth of the melanoma PDOX (P = 0. 001). Salmonella A1-R has future clinical potential for combination chemotherapy with CDDP of melanoma, a highly-recalcitrant cancer

Gender dimorphism and age of onset in malignant peripheral nerve sheath tumor preclinical models and human patients.

BackgroundGender-based differences in disease onset in murine models of malignant peripheral nerve sheath tumor (MPNST) and in patients with Neurofibromatosis type-1-(NF-1)-associated or spontaneous MPNST has not been well studied.MethodsForty-three mGFAP-Cre+;Ptenloxp/+;LSL-K-rasG12D/+ mice were observed for tumor development and evaluated for gender disparity in age of MPNST onset. Patient data from the prospectively collected UCLA sarcoma database (1974-2011, n = 113 MPNST patients) and 39 published studies on MPNST patients (n = 916) were analyzed for age of onset differences between sexes and between NF-1 and spontaneous MPNST patients.ResultsOur murine model showed gender-based differences in MPNST onset, with males developing MPNST significantly earlier than females (142 vs. 162 days, p = 0.015). In the UCLA patient population, males also developed MPNST earlier than females (median age 35 vs. 39.5 years, p = 0.048). Patients with NF-1-associated MPNST had significantly earlier age of onset compared to spontaneous MPNST (median age 33 vs. 39 years, p = 0.007). However, expanded analysis of 916 published MPNST cases revealed no significant age difference in MPNST onset between males and females. Similar to the UCLA dataset, patients with NF-1 developed MPNST at a significantly younger age than spontaneous MPNST patients (p < 0.0001, median age 28 vs. 41 years) and this disparity was maintained across North American, European, and Asian populations.ConclusionsAlthough our preclinical model and single-institution patient cohort show gender dimorphism in MPNST onset, no significant gender disparity was detected in the larger MPNST patient meta-dataset. NF-1 patients develop MPNST 13 years earlier than patients with spontaneous MPNST, with little geographical variance

Comprehensive adipocytic and neurogenic tissue microarray analysis of NY-ESO-1 expression - a promising immunotherapy target in malignant peripheral nerve sheath tumor and liposarcoma.

BackgroundImmunotherapy targeting cancer-testis antigen NY-ESO-1 shows promise for tumors with poor response to chemoradiation. Malignant peripheral nerve sheath tumors (MPNSTs) and liposarcomas (LPS) are chemoresistant and have few effective treatment options. Materials Methods: Using a comprehensive tissue microarray (TMA) of both benign and malignant tumors in primary, recurrent, and metastatic samples, we examined NY-ESO-1 expression in peripheral nerve sheath tumor (PNST) and adipocytic tumors. The PNST TMA included 42 MPNSTs (spontaneous n = 26, NF1-associated n = 16), 35 neurofibromas (spontaneous n = 22, NF-1 associated n = 13), 11 schwannomas, and 18 normal nerves. The LPS TMA included 48 well-differentiated/dedifferentiated (WD/DD) LPS, 13 myxoid/round cell LPS, 3 pleomorphic LPS, 8 lipomas, 1 myelolipoma, and 3 normal adipocytic tissue samples. Stained in triplicate, NY-ESO-1 intensity and density were scored.ResultsNY-ESO-1 expression was exclusive to malignant tumors. 100% of myxoid/round cell LPS demonstrated NY-ESO-1 expression, while only 6% of WD/DD LPS showed protein expression, one of which was WD LPS. Of MPNST, 4/26 (15%) spontaneous and 2/16 (12%) NF1-associated MPNSTs demonstrated NY-ESO-1 expression. Strong NY-ESO-1 expression was observed in myxoid/round cell and dedifferentiated LPS, and MPNST in primary, neoadjuvant, and metastatic settings.ConclusionsWe found higher prevalence of NY-ESO-1 expression in MPNSTs than previously reported, highlighting a subset of MPNST patients who may benefit from immunotherapy. This study expands our understanding of NY-ESO-1 in WD/DD LPS and is the first demonstration of staining in a WD LPS and metastatic/recurrent myxoid/round cell LPS. These results suggest immunotherapy targeting NY-ESO-1 may benefit patients with aggressive tumors resistant to conventional therapy

Pathologic Response to Neoadjuvant Therapy is Associated With Improved Long-term Survival in High-risk Primary Localized Malignant Peripheral Nerve Sheath Tumors.

BACKGROUND:Malignant peripheral nerve sheath tumors (MPNSTs) comprise a rare, aggressive subtype of soft tissue sarcoma. While surgery is the mainstay of therapy for this disease, the role of neoadjuvant therapy remains undefined. METHODS:This study reviewed patients 16 years of age and older who underwent surgical treatment for MPNST between 1974 and 2012 at the authors' institution. Univariate and multivariate analyses were performed of clinicopathologic and treatment variables predictive of disease-specific survival (DSS) and disease-free survival. RESULTS:Eighty-eight patients with primary localized MPNST underwent surgical treatment between 1974 and 2012 at our institution. Of these, 38 (43%) underwent neoadjuvant chemotherapy and had tissue available for analysis. Neoadjuvant radiation was given to 25 patients (68%). The median follow-up time for survivors was 12.5 years (range, 4 to 27 y). Nine patients (23%) had underlying MPNST. With a cutoff of ≥90% pathologic necrosis and/or fibrosis defining response, we identified 14 responders (36%). On univariate analysis, patient age, tumor size, and pathologic response were significantly associated with DSS (P=0.015, 0.011, and 0.030, respectively). CONCLUSIONS:Although the impact of neoadjuvant chemotherapy on the outcome of primary localized MPNST patients continues to be debated, this study shows that a pathologic response to therapy is associated with a significant improvement in DSS. The challenge moving forward is to determine upfront which patients will be "responders" to standard systemic therapy and which patients should be considered for newer investigational agents as part of a clinical trial

<i>Salmonella</i> A1-R targeting and efficacy on the melanoma PDOX model.

<p><b>A)</b> Schematic diagram of the experimental protocol. <b>B)</b> Efficacy of <i>Salmonella</i> A1-R is indicated by the volume ratio of the transplanted tumor at day 28 after injection compared with the tumor at the beginning of the treatment. Tumor size of the <i>Salmonella</i> A1-R-treated group was significantly decreased compared with the untreated control group. The values are mean relative tumor volume ± SEM (bars). There were five mice per group. *<i>p</i> < 0.05 compared to the untreated group. <b>C)</b> Distribution of GFP-labeled <i>Salmonella</i> A1-R in tumor and organs. Representative images of GFP-labeled <i>Salmonella</i> A1-R bacteria isolated and cultured from the tumor and the normal organs (blood, liver and spleen) of the mice treated with <i>Salmonella</i> A1-R. Fluorescence imaging with the iBox small animal imaging system (UVP LLC). Scale bar: 10 mm. <b>D)</b> Colony number of each sample is indicated per mg of harvested tissue. Tissues were collected from three different mice. GFP-labeled <i>Salmonella</i> A1-R was clearly detected in the tumor. A small number of GFP-labeled <i>Salmonella</i> A1-R was detected in the liver and no GFP-labeled <i>Salmonella</i> A1-R was detected in blood and spleen.</p

Establishment of a melanoma patient-derived orthotopic xenograft (PDOX) model.

<p><b>A)</b> Schematic diagram of the experimental protocol. <b>B)</b> Representative cross-sections of transplanted tumor 28 days after transplantation obtained from an orthotopically-transplanted patient’s melanoma. Scale bar: 10 mm. <b>C)</b> Immunohistochemical characterization of PDOX melanoma after being grown in nude mice. H&E-stained sections (left column) and immunohistochemistry for human MHC class I (HLA; middle column) and mouse MHC class I (H2 KdtH2 Dd; right column). Strong staining for HLA was observed in the cancer cells (middle column), whereas strong staining for H2 KdtH2 Dd was observed in the stromal cells (right column). Magnified views of boxed region in the upper rows are indicated at the middle rows and magnified views of boxed region in the middle rows are indicated in the lower rows. Black arrowhead indicates necrotic region of the tumor. Scale bars: (top and middle row) 200 μm; (bottom row) 100 μm.</p

Effect of a tumor-targeting <i>Salmonella</i> A1-R and chemotherapy on the melanoma PDOX.

<p><b>A)</b> Schematic diagram of the experimental protocol. (1) untreated control (Control); (2) 5-fluorouracil (5-FU; 10 mg/kg, intraperitoneal injection (i.p.), qW×4); (3) cisplatinum (CDDP; 5 mg/kg, i.p., qW×4); (4) <i>Salmonella</i> A1-R (5 × 10⁷ CFU/body, intravenously (i.v.), qW×4) and (5) <i>Salmonella</i> A1-R (3 × 10⁷ CFU/body, i.v., qW×4) + CDDP (CDDP; 3 mg/kg, i.p., qW×4). <b>B)</b> Growth curves of the melanoma PDOX tumor treated with various drugs as described above. B1: Mean change in tumor volume plotted against time; Control, <i>n</i> = 9; 5-FU, <i>n</i> = 4; CDDP, <i>n</i> = 5; <i>Salmonella</i> A1-R, <i>n</i> = 9; <i>Salmonella</i> A1-R + CDDP, <i>n</i> = 8. B-2: Data plotted are linear prediction versus time with adjusted predictions of interaction of treatment group and time with 95% Cis. The treatment-by-time interaction was significant (p = 0.0000) as were the main-effects for treatment and time (p = 0.0000) for <i>Salmonella</i> A1-R, CDDP and <i>Salmonella</i> A1-R and CDDP combined. <b>C)</b> Comparison of body weight of nude mice transplanted PDOX tumors after <i>Salmonella</i> A1-R and/or chemotherapy. All values represent mean ± SEM; Control, <i>n</i> = 8; 5-FU, <i>n</i> = 4; CDDP, <i>n</i> = 4; <i>Salmonella</i> A1-R, <i>n</i> = 7; <i>Salmonella</i> A1-R + CDDP, <i>n</i> = 4. **<i>p</i> < 0.01, compared with the untreated control group.</p