Co-targeting PI3K, mTOR, and IGF1R with small molecule inhibitors for treating undifferentiated pleomorphic sarcoma.

Undifferentiated pleomorphic sarcomas (UPSs) are aggressive mesenchymal malignancies with no definitive cell of origin or specific recurrent genetic hallmarks. These tumors are largely chemoresistant; thus, identification of potential therapeutic targets is necessary to improve patient outcome. Previous studies demonstrated that high expression of activated protein kinase B (AKT) in patients with UPS corresponds to poor disease-specific survival. Here, we demonstrate that inhibiting phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) signaling using a small molecule inhibitor reduced UPS cell proliferation and motility and xenograft growth; however, increased phosphorylation of insulin-like growth factor 1 receptor (IGF1R) indicated the potential for adaptive resistance following treatment through compensatory receptor activation. Co-treatment with a dual PI3K/mTOR inhibitor and an anti-IGF1R kinase inhibitor reduced in vivo tumor growth rates despite a lack of antiproliferative effects in vitro. Moreover, this combination treatment significantly decreased UPS cell migration and invasion, which is linked to changes in p27 subcellular localization. Our results demonstrate that targeted inhibition of multiple components of the IGF1R/PI3K/mTOR pathway was more efficacious than single-agent therapy and suggest that co-targeting this pathway could be a beneficial therapeutic strategy for patients with UPS.

Patterns of recurrence and survival in sporadic, neurofibromatosis Type 1-associated, and radiation-associated malignant peripheral nerve sheath tumors.

OBJECTIVE Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive group of soft tissue sarcomas that can arise sporadically, in the context of neurofibromatosis Type 1 (NF1) or at a site of prior irradiation. Large series profiling the features and outcomes of sporadic, NF1-associated, and radiation-associated MPNSTs are limited. The goal of this study was to elucidate differences between MPNST etiologies in a large single-institution retrospective study. METHODS Patients (n = 317) were identified through the tumor registry of The University of Texas MD Anderson Cancer Center. Clinicopathological features were retrospectively collected. Features were compared among MPNST subtypes for patients who had sufficient clinical history (n = 289), and clinicopathological features were used to identify adverse predictors of recurrence and survival outcomes. RESULTS Five-year local recurrence-free survival (LRFS), distant recurrence-free survival (DRFS), and disease-specific survival (DSS) estimates were 56.6%, 49.6%, and 53.6%, respectively, for the high-grade MPNST cohort. Five-year DSS was lower in NF1-associated and radiation-associated MPNST than in sporadic MPNST (52%, 47%, and 67%, respectively, p = 0.140). Patients with radiation-associated MPNST had worse 5-year LRFS than those with the sporadic and NF1-associated subtypes (RT-associated vs sporadic, p = 0.010; RT-associated vs NF1-associated, p = 0.232). Truncally located tumors, positive surgical margins, local recurrence, and metastasis were predictors of adverse DSS in multivariate analysis. CONCLUSIONS Radiation-associated MPNSTs are associated with poorer local recurrence-free and disease-specific survival than sporadic and NF1-associated tumors. NF1-associated MPNSTs may have worse survival outcomes owing to large tumor size, compromising truncal location, and lower rate of negative resection margins compared with sporadic tumors.

Sarcoma Brain Metastases: 28 Years of Experience at a Single Institution.

BACKGROUND: Brain metastasis from sarcoma is rare, thus limited information is available. We examined sarcoma brain metastases diagnosed at our institution over a period of 28 years. METHODS: This is a retrospective study of 112 cases. Clinical records were reviewed and clinical, pathological, and survival data were tabulated. RESULTS: Undifferentiated sarcoma was the most common source. In 50 % of cases, the primary sarcoma was in the extremities. Most patients were adults at the time of first brain metastasis, and median age was 34.8 years. Although most patients evidenced metastatic disease to other sites prior to developing brain metastasis, in almost one quarter, brain was the initial site. Most of the metastatic foci were parenchymal, nonhemorrhagic, and solitary. Forty percent of the brain metastatic deposits were located in the frontal lobes. Thirty-one percent recurred-all within 5.3 years. Seventy-six percent of patients succumbed to the disease, with a median survival time of only 0.6 years. Hemorrhagic metastatic foci were found to be associated with significantly lower recurrence-free, as well as disease-specific survivals. No difference in survival was noted between single versus multiple deposits or primary soft tissue versus bone sarcomas. No statistically significant effect on survival was found when neurosurgical resection was combined with radiotherapy. Chemotherapy, on the other hand, was found to significantly improve disease-specific survival when combined with metastasectomy. CONCLUSIONS: Undifferentiated sarcoma was the most common source of brain metastasis. Most cases showed evidence of prior metastatic disease. Surgical resection is employed to manage symptoms, but prognosis remains dismal.

Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival.

Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that can show overlapping features with benign neurofibromas as well as high-grade sarcomas. Additional diagnostic markers are needed to aid in this often challenging differential diagnosis. Recently mutations in two critical components of the polycomb repressor 2 (PRC2) complex, SUZ12 and EED, were reported to occur specifically in MPNSTs while such mutations are absent in neurofibromas, both in the setting of neurofibromatosis (NF) and sporadic cases. Furthermore, both SUZ12 and EED mutations in MPNSTs were associated with loss of H3K27 tri-methylation, a downstream target of PRC2. Therefore, we tested whether H3K27me3 immunohistochemistry is useful as a diagnostic and prognostic marker for MPNSTs. We performed H3K27me3 immunohistochemistry in 162 primary MPNSTs, 97 neurofibromas and 341 other tumors using tissue microarray. We observed loss of H3K27me3 in 34% (55/162) of all MPNSTs while expression was retained in all neurofibromas including atypical (n=8) and plexiform subtypes (n=24). Within other tumors we detected loss of H3K27me3 in only 7% (24/341). Surprisingly, 60% (9/15) of synovial sarcomas and 38% (3/8) of fibrosarcomatous dermatofibrosarcoma protuberans (DFSP) showed loss of H3K27 trimethylation. Only 1 out of 44 schwannomas showed loss of H3K27me3 and all 4 perineuriomas showed intact H3K27me3. Furthermore, MPNSTs with loss of H3K27 tri-methylation showed inferior survival compared with MPNSTs with intact H3K27 tri-methylation, which was validated in two independent cohorts. Our results indicate that H3K27me3 immunohistochemistry is useful as a diagnostic marker, in which loss of H3K27me3 favors MPNST above neurofibroma. However, H3K27me3 immunohistochemistry is not suitable to distinguish MPNST from its morphological mimicker synovial sarcoma or fibrosarcomatous DFSP. Since loss of H3K27 tri-methylation was related to poorer survival in MPNST, chromatin modification mediated by this specific histone seems to orchestrate more aggressive tumour biology.

Analysis of Clinical and Molecular Factors Impacting Oncologic Outcomes in Undifferentiated Pleomorphic Sarcoma.

BACKGROUND: Undifferentiated pleomorphic sarcomas (UPS) present a diagnostic and therapeutic challenge. Identification of prognostic molecular markers is required for the discovery of novel treatment approaches. The purpose of this study was to correlate clinicopathologic variables, expression of tyrosine kinase receptors, and markers of cell cycle progression and survival with oncologic outcomes. METHODS: A tissue microarray containing 208 primary UPS samples was analyzed by immunohistochemistry for protein markers and in situ hybridization for microRNA. Staining results were correlated with clinicopathologic features and oncologic outcomes. Univariate and multivariate analyses were conducted to assess associations between expression of protein markers, mi-RNA, and outcome. RESULTS: At a median follow-up of 3.9 years (9 years for survivors), 5-year disease-specific survival (DSS) was 63 %. Clinical variables associated with improved DSS included age <61 years, tumor size <10 cm, margin-negative resection, and sporadic-tumor status. At the protein level, loss of cyclin D1 (p = 0.06), pEGFR (p = 0.023), pIGF-1R (p = 0.022), and PTEN (p < 0.001) and overexpression of AXL (p = 0.015) were associated with reduced DSS on univariate analysis. Ki67, PCNA, and pEGFR were more highly expressed in sporadic UPS than radiation-associated (RA-UPS), whereas RA-UPS samples expressed higher levels of both phosphorylated and total IGF-1R. DISCUSSION: Loss of cyclin D1, overexpression of AXL, and loss of PTEN are associated with poor cancer-specific outcomes and warrant further investigation in UPS. The differences in protein expression in sporadic versus RA-UPS may indicate that the activated molecular signaling nodes may be different for each specific histology and also could explain the aggressive phenotype seen in RA-UPS compared with the sporadic lesions.

Poly (ADP) ribose polymerase inhibition: A potential treatment of malignant peripheral nerve sheath tumor.

Poly (ADP) ribose polymerase (PARP) inhibitors, first evaluated nearly a decade ago, are primarily used in malignancies with known defects in DNA repair genes, such as alterations in breast cancer, early onset 1/2 (BRCA1/2). While no specific mutations in BRCA1/2 have been reported in malignant peripheral nerve sheath tumors (MPNSTs), MPNST cells could be effectively targeted with a PARP inhibitor to drive cells to synthetic lethality due to their complex karyotype and high level of inherent genomic instability. In this study, we assessed the expression levels of PARP1 and PARP2 in MPNST patient tumor samples and correlated these findings with overall survival. We also determined the level of PARP activity in MPNST cell lines. In addition, we evaluated the efficacy of the PARP inhibitor AZD2281 (Olaparib) in MPNST cell lines. We observed decreased MPNST cell proliferation and enhanced apoptosis in vitro at doses similar to, or less than, the doses used in cell lines with established defective DNA repair genes. Furthermore, AZD2281 significantly reduced local growth of MPNST xenografts, decreased the development of macroscopic lung metastases, and increased survival of mice with metastatic disease. Our results suggest that AZD2281 could be an effective therapeutic option in MPNST and should be further investigated for its potential clinical use in this malignancy.

Progressive loss of myogenic differentiation in leiomyosarcoma has prognostic value.

AIMS: Well-differentiated leiomyosarcomas show morphologically recognizable smooth muscle differentiation, whereas poorly differentiated tumours may form a spectrum with a subset of undifferentiated pleomorphic sarcomas. The expression of certain muscle markers has been reported to have prognostic impact. We investigated the correlation between the morphological spectrum and the muscle marker expression profile of leiomyosarcoma, and the impact of these factors on patient outcomes. METHODS AND RESULTS: Tissue microarrays including 202 non-uterine and 181 uterine leiomyosarcomas with a spectrum of tumour morphologies were evaluated for expression of immunohistochemical markers of muscle differentiation. Poorly differentiated tumours frequently lost one or more conventional smooth muscle markers [smooth muscle actin, desmin, h-caldesmon, and smooth muscle myosin (P < 0.0001)], as well as the more recently described markers SLMAP, MYLK, and ACTG2 (P < 0.0001). In primary tumours, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (P = 0.0111 and P = 0.043, respectively). Patients with muscle marker-enriched tumours (expressing all four conventional markers or any three of ACTG2, CFL2, CASQ2, MYLK, and SLMAP) had improved overall survival (P < 0.05) in univariate analyses. CONCLUSIONS: Morphologically and immunohistochemically, poorly differentiated leiomyosarcomas can masquerade as undifferentiated pleomorphic sarcomas with progressive loss of muscle markers. The expression of muscle markers has prognostic significance in primary leiomyosarcomas independently of tumour morphology.