sirolimus and Hemangiosarcoma

Angiosarcoma is a rare, almost universally fatal malignant neoplasm in kidney transplant recipients. No evidence-based guidelines are available for disseminated disease. Here, we report a case of a 66-year-old woman who developed disseminated angiosarcoma 4 months after living nonrelated kidney transplant. She underwent only 2 rounds of chemotherapy because of intolerable adverse effects. Her mycophenolic acid and tacrolimus were withdrawn and sirolimus use was started. In addition to its immunosuppressant effects, sirolimus has been shown to have antineoplastic properties. Remarkably, at almost 2 years post-transplant, the patient has had complete resolution of all gross metastatic disease with only immunosuppressant medication changes. This case highlights the interesting possibility that sirolimus is an effective adjunct treatment for disseminated angiosarcoma in kidney transplant recipients.

Topics: Aged; Female; Graft Rejection; Hemangiosarcoma; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus

Tuberous sclerosis complex (TSC) is an autosomal disease caused by inactivating mutations in either of the tumor suppressor genes TSC1 or TSC2. TSC-associated tumor growth is present in multiple tissues and organs including brain, kidney, liver, heart, lungs, and skin. In the kidney, TSC angiomyolipomas have aberrant vascular structures with abnormal endothelial cells, suggesting a role for endothelial mTORC1 function. In the current report, a genetically engineered mouse model (GEMM) with a conditional knockout allele of Tsc1 with a Darpp32-Cre allele displayed accelerated formation of both kidney cystadenomas and paw hemangiosarcomas. All mutant mice developed hemangiosarcomas on multiple paws by 6 weeks of age. By 16 weeks of age, the average mutant hind paw was 4.0 mm in diameter, nearly double the size of control mice. Furthermore, the hemangiosarcomas and kidney cystadenomas were responsive to intraperitoneal rapamycin treatment. Immunoblotting and immunostaining for phospho-S6 (pS6) and phospho-CAD showed that the effect of rapamycin on tumor size was through inhibition of the mTOR signaling pathway. Finally, elevated VEGF mRNA levels were also observed in hemangiosarcoma specimens. Because paw hemangiosarcomas are easily detectable and scorable for size and growth, this novel mouse model enables accelerated in vivo drug testing for therapies of TSC-related tumors.. These findings provide a strong rationale for simultaneous use of this conditional knockout mouse as an in vivo genetic model while seeking new cancer therapies for TSC-related tumors.

Topics: Animals; Antibiotics, Antineoplastic; Cystadenoma; Dopamine and cAMP-Regulated Phosphoprotein 32; Hemangiosarcoma; Injections, Intraperitoneal; Kidney Neoplasms; Mechanistic Target of Rapamycin Complex 1; Mice; Multiprotein Complexes; Neoplasms, Experimental; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tuberous Sclerosis Complex 1 Protein; Tumor Suppressor Proteins; Up-Regulation; Vascular Endothelial Growth Factor A

Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition. However, treatment with nanomolar levels of mTOR inhibitor renders these cells as sensitive to MEK inhibition as a melanoma cell line with mutant BRAF. Similar results were observed in B-Raf wild-type melanoma cells as well as in vivo, where treatment of canine AS tumorgrafts with MEK and mTOR inhibitors was more effective than monotherapy. Our data show that a low dose of an mTOR inhibitor can dramatically enhance angiosarcoma and melanoma response to MEK inhibition, potentially widening the field of applications for MEK-targeted therapy.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Diphenylamine; Dogs; Dose-Response Relationship, Drug; Drug Synergism; Hemangiosarcoma; Humans; Melanoma; Mice; Mitogen-Activated Protein Kinase Kinases; Sirolimus; TOR Serine-Threonine Kinases; Xenograft Model Antitumor Assays

Angiosarcomas are rare, aggressive vascular tumours known to express vascular endothelial growth factor (VEGF), a key pro-angiogenic growth factor. The aim of this study was to determine the potential effects of vascular-targeted agents for the treatment of angiosarcoma, using two human cutaneous angiosarcoma cell lines (ASM and ISO-HAS), and human dermal microvascular endothelial cells (HuDMECs) for comparison.. Protein arrays were used to assess the expression of angiogenesis-related proteins, and potential drug targets were assessed by ELISA and Western blotting. Response to vascular-targeted agents, including bevacizumab an anti-VEGF antibody, axitinib a VEGF-receptor tyrosine kinase inhibitor, everolimus an mTOR inhibitor, selumetinib a MEK inhibitor and vadimezan a vascular-disrupting agent were compared in functional in vitro cellular assays, including viability, differentiation and migration assays.. ASM and ISO-HAS cells expressed a broad range of pro-angiogenic growth factors. ASM and ISO-HAS VEGF expression was significantly increased (p = 0.029) compared with HuDMECs. Striking responses were seen to vadimezan with an IC50 of 90 and 150 μg/ml for ASM and ISO-HAS cells, respectively. Selumetinib inhibited ASM with an IC50 of 1,750 ng/ml, but was not effective in ISO-HAS. Everolimus reduced both ASM and ISO-HAS viable cell counts by 20 % (p < 0.001). Minimal responses were observed to bevacizumab and axitinib in assays with ASM and ISO-HAS cells.. Further studies are warranted to investigate mTOR inhibitors, MEK inhibitors and vascular-disrupting agents for the treatment of angiosarcoma.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Axitinib; Bevacizumab; Cell Death; Cell Differentiation; Cell Line, Tumor; Cell Movement; Doxorubicin; Everolimus; Hemangiosarcoma; Humans; Imidazoles; Indazoles; Neovascularization, Pathologic; Paclitaxel; Protein Array Analysis; Sirolimus; Vascular Endothelial Growth Factor A

Malignant liver tumors represent approximately 1% of malignancies in children. HA is a high-grade tumor of endothelial cells that is even more rare in the pediatric population. HA has a limited response to chemotherapy, radiation and resection with universal tumor recurrence with LT and nearly 100% mortality by 18 months. This is the first reported successful case of hepatic angiosarcoma in a child who was treated by LT in combination with sirolimus. Sirolimus antagonizes the mTOR pathway, which regulates cell proliferation, differentiation, and migration, and is being studied as an anti-neoplastic agent for solid tumors.

Topics: Antibiotics, Antineoplastic; Chemotherapy, Adjuvant; Child, Preschool; Female; Hemangiosarcoma; Humans; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Sirolimus

Vascular tumors are endothelial cell neoplasms whose cellular and molecular mechanisms, leading to tumor formation, are poorly understood, and current therapies have limited efficacy with significant side effects. We have investigated mechanistic (mammalian) target of rapamycin (mTOR) signaling in benign and malignant vascular tumors, and the effects of mTOR kinase inhibitor as a potential therapy for these lesions. Human vascular tumors (infantile hemangioma and angiosarcoma) were analyzed by immunohistochemical stains and western blot for the phosphorylation of p70 S6-kinase (S6K) and S6 ribosomal protein (S6), which are activated downstream of mTOR complex-1 (mTORC1). To assess the function of S6K, tumor cells with genetic knockdown of S6K were analyzed for cell proliferation and migration. The effects of topical rapamycin, an mTOR inhibitor, on mTORC1 and mTOR complex-2 (mTORC2) activities, as well as on tumor growth and migration, were determined. Vascular tumors showed increased activation of S6K and S6. Genetic knockdown of S6K resulted in reduced tumor cell proliferation and migration. Rapamycin fully inhibited mTORC1 and partially inhibited mTORC2 activities, including the phosphorylation of Akt (serine 473) and PKCα, in vascular tumor cells. Rapamycin significantly reduced vascular tumor growth in vitro and in vivo. As a potential localized therapy for cutaneous vascular tumors, topically applied rapamycin effectively reduced tumor growth with limited systemic drug absorption. These findings reveal the importance of mTOR signaling pathways in benign and malignant vascular tumors. The mTOR pathway is an important therapeutic target in vascular tumors, and topical mTOR inhibitors may provide an alternative and well-tolerated therapy for the treatment of cutaneous vascular lesions.

Topics: Administration, Topical; Adolescent; Adult; Aged; Animals; Antibiotics, Antineoplastic; Cell Line, Tumor; Child; Female; Hemangioma, Capillary; Hemangiosarcoma; Humans; Infant; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Nude; Multiprotein Complexes; Neoplasm Proteins; Neoplastic Syndromes, Hereditary; Protein Kinase Inhibitors; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; TOR Serine-Threonine Kinases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

Beyond their primary field of application some well-established drugs exhibit antitumour effects in a variety of cancers. The aim of this study was to investigate the effects of the COX2 inhibitor celecoxib and the mTOR antagonist rapamycin on angiosarcoma cell lines.. Cell proliferation was measured in ASM, ISOS 1 and ISO HAS angiosarcoma cell lines with the BrdU assay.. In all angiosarcoma cell lines, celecoxib as well as rapamycin inhibited cell growth in a dose-dependent manner. In ASM and ISOS 1, but not in ISO HAS angiosarcoma cells, additive growth inhibitory effects were detected by combining both agents.. Our results indicate that angiosarcoma cell proliferation can be inhibited by subtoxic doses of rapamycin and celecoxib. Due to their direct and stroma-mediated anticancer activities, mTOR antagonists and COX2 inhibitors represent very promising drugs in the palliative treatment of angiosarcoma.

Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Celecoxib; Cell Growth Processes; Cell Line, Tumor; Cyclooxygenase 2 Inhibitors; Dose-Response Relationship, Drug; Drug Synergism; Hemangiosarcoma; Humans; Mice; Pyrazoles; Sirolimus; Sulfonamides

The PIK3CA gene, coding for the catalytic subunit p110alpha of class IA phosphatidylinositol 3-kinases (PI3Ks), is frequently mutated in human cancer. Mutated p110alpha proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110alpha, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110alpha mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies.

Topics: Animals; Antineoplastic Agents; Blotting, Western; Cell Membrane; Cells, Cultured; Chick Embryo; Chickens; Chorioallantoic Membrane; Class I Phosphatidylinositol 3-Kinases; Disease Models, Animal; Hemangiosarcoma; Humans; Microglia; Mutation; Neoplasms; Phosphatidylinositol 3-Kinases; Placebos; Signal Transduction; Sirolimus; Time Factors; Transfection