TARGETED THERAPIES IN RARE

SARCOMASSilvia Stacchiotti, Andrea Marrari

Hematology Oncology Clinics of North America Volume 27 (2013); 1049-1061

• Inflammatory Myofibroblastic Tumor (IMT)

• Alveolar Soft-Part Sarcoma (ASPS)

• Solitary Fibrous Tumor (SFT)

• Perivascular Epitheloid Cell Tumor (PEComa)

• Clear Cell Sarcoma (CCS)

INFLAMATORY MYOFIBROBLASTIC TUMOR

• Mesenchymal spindle cell neoplasm associated with plasma cells, lymphocytes and granulocytes

• Low grade sarcoma arising in lung, mesentery, retroperitoneum and pelvis

• Children and young adults

• High propensity of local recurrence

• Rarely metastasize

• Associated with recurrent clonal aberration involving ALK locus on chromosome 2p23

• ALK :

• Receptor tyrosine kinase

• Involved in normal development and functioning of nervous system

• Hyperactivation : Uncontrolled cell growth

• More aggressive variants are not associated with ALK mutation

INFLAMATORY MYOFIBROBLASTIC TUMOR

• Treatment :

• Surgery

• Unresectable :

• Steroids

• Chemotherapy

INFLAMATORY MYOFIBROBLASTIC TUMOR

• Molecular target agents :

• Crizotinib (ALK/MET inhibitor)

• Only agent found beneficial

• Mechanism of action : Competitive inhibition of the ATP binding site of both kinases

• Proven efficacy in Phase I trials with ALK mutation positive disease with sustained partial response

• Phase II trial undergoing (NCT01524926)

INFLAMATORY MYOFIBROBLASTIC TUMOR

ALVEOLAR SOFT TISSUE SARCOMA

• Epitheloid cell population organised in an alveolar growth pattern

• Affects mainly young adults

• Indolent behaviour

• > 60% risk of metastasis at 10 years

• Characterised by an unbalanced recurrent translocation t(x;17)(p11;q25)

• MET transcription upregulation by transcription factor ASPL-TFE3

• Expression of Vascular Endothelial growth factor (VEGFR) and Platelet derived growth factor receptors (PDGFR) on both tumor vessels and tumor cells

ALVEOLAR SOFT TISSUE SARCOMA

• Treatment :

• Surgery

• Highly resistant to conventional chemotherapy – No standard active medical options available in advanced stages

ALVEOLAR SOFT TISSUE SARCOMA

• Molecular agents :

• MET inhibitors :

• Tivantinib (ARC197)

• Crizotinib

• Anti angiogenic agents

• Interferon-alfa

• Bevacizumab

• Sunitinib

• Cediranib

ALVEOLAR SOFT TISSUE SARCOMA

SOLITARY FIBROUS TUMOR

• Initially reportd as primary mesenchymal tumor of pleura – Beningn localized Mesothelioma

• Complete genetic and morphological overlap with Hemangiopericytoma

• NAB2-STAT6 gene fusion

• Three clinico-pathological variants :

• Classical Soft Fibrous Tumor (CSFT)

• Malignant Solitary Fibrous Tumor (MSFT)

• Dedifferentiated Solitary Fibrous Tumor (DSFT)

• Expression of :

• Platelet derived growth factor receptor (PDGFR)

• MET

• ERBB2

• FGFR1

• Insulin like growth factor 2 (IGF2)

SOLITARY FIBROUS TUMOR

• High cure rate after surgery

• 10-15% risk of metastasis

• DSTF – More aggressive behaviour with higher metastatic potential

• No much response seen with Doxorubicin

SOLITARY FIBROUS TUMOR

• Molecular target agents :

• Antiangiogenics :

Bevacizumab (in combination with Temozolamide)

Sorafenib

Sunitinib

Pazopanib

• IGF1R Inhibitors

Figitumomab (in combination with Everolimus)

Cituxumomab (in combination with Temsirulimus)

SOLITARY FIBROUS TUMOR

PERIVASCULAR EPITHELOID CELL TUMOR

• Rare mesenchymal tumors with myomelanocytic diffentiation

• Distinctive cell type : Perivascular Epitheloid cell (PEC)

• Expresses both smooth muscle and melanocytic markers

• Family includes :

• Angiomyolipoma (AML)

• Lymphangioleiomyomatosis (LAM)

• Clear cell sugar tumor of Lung

• PEComa

• PEComas associated with Tuberous Sclerosis complex

• Inactivation of TSC1 or TSC2 tumor suppressor genes

• TSC1/TSC2 complex inhibits proliferative signals of mTOR complex 1 through inhibition of Rheb (GTP hydrolase enzyme)

PERIVASCULAR EPITHELOID CELL TUMOR

• Treatment :

• Surgery for localized disease

• Anthracycline or Gemcitabine based chemotherapy in advanced disease (Unsatisfactory Response Rates)

• Malignant PEComas may recur or metastasize

PERIVASCULAR EPITHELOID CELL TUMOR

• Molecular target agents :

• mTOR Inhibitors

Rapamycin

Temsirolimus

Everolimus

Ridaforolimus

• Responses are short lived

• Median Progression free survival of 4 months

• Primary resistance also seen in few cases

PERIVASCULAR EPITHELOID CELL TUMOR

CLEAR CELL SARCOMA

• Very rare soft tissue sarcoma

• Adolescents and young adults

• Any site of body

• In GI tract – Malignant neuroectodermal tumor

• Morphological and Immunohistochemical features overlapping with Malignant melanoma

• Two recurrent translocations seen in Clear cell sarcoma an not seen in malignant melanoma

• t(12;22)(q13;q12) – EWSR1 and ATF1 gene fusion

• t(2;22)(q34;q12) - EWSR1 and CREB1 gene fusion

• Very aggressive behaviour

• >60% incidence of metastasis

• Very poor prognosis

• Poor sensitivity to chemotherapy

CLEAR CELL SARCOMA

• Molecular target agents

• Yet to be identified

• MET inhibitors and antiangiogenics have shown some degree of activity

CLEAR CELL SARCOMA

EMERGING THERAPIES FOR SOFT TISSUE

SARCOMASAlice Levard, Phillppe A Cassier

Hematology Oncology Clinics of North America Volume 27(2013); 1063-1078

• BROAD SPECTRUM APPROACHES

• SUBTYPE-SPECIFIC APPROACHES

• OTHER APPROACHES

BROAD SPECTRUM APPROACHES

• Cytotoxic Agents

• Targeting Angiogenesis

• Targeting the PI3K-Akt-mTOR Pathway and IGF1R

• Histone Deacetylase Inhibitors

• Hedgehog and Notch Signalling

Cytotoxic Agents

• Palifosfamide

• Eribulin mesylate

• Inhibitor of micro tubulin dynamics

• Good results in Phase II Trials done by EORTC – Progression free survival at 12 weeks

• Phase III trial : Eribulin with Dacarbazine in Liposarcoma and Leimyosarcoma

• TH 302

• DNA alkylator

• Phase I/II studies have shown good response rates in advanced soft tissue sarcomas in commination with Doxorubicin

• Phase III trial of Doxorubicin with or without TH 302 in underway

• Aldoxorubicin (INNO 206)

• Doxorubicin conjugate

• Mechanism of action : Following intravenous injection, aldoxorubicin binds to albumin and accumulates in tumor sites to release doxorubicin

• Increasing therapeutic ratio of doxorubicin

• Phase II trial underway

Cytotoxic Agents

Targeting Angiogenesis

• Pazopanib : Approved for use in soft tissue sarcomas

• Sunitinib : Not found to be effective

• Sorafenib : Good results in Phase II trials

• Phase I/II Trials have been done combining Sorafenib with Ifosfamide/Dacarbazine

• Benefit of combining this drug with other chemotherapeutic agents still not confirmed

• No benefit seen in combination with Radiation Therapy

• Bevacizumab

• Has shown efficacy in combination with Gemcitabine and Docetaxel in Phase II trials (Response rates – 31.5%)

• Phase III trials underway

• Not found beneficial in combination with Doxorubicin in Phase II trials (Response rates – 12% with high Cardiac toxicity)

• Good pathological response seen in combination with Radiotherapy

• Brivanib

• Tyrosine Kinase inhibitor targeting Vascular Endothelial growth factor receptor (VEGFR) and Fibroblast growth factor receptor (FGFR) kinases

• Not found effective in Phase II trials

Targeting Angiogenesis

Targeting the PI3A-Akt-mTOR Pathway and IGF1R

• PI3A-Akt-mTOR Pathway :

• Plays a role in sarcomageneis and prognosis of soft tissue sarcomas

• Rapalogues : Analogues of Rapamycin

• Ridaforolimus

• Temsirolimus

• Sirolimus

• Not found beneficial

• IGF1R (Insulin like Growth factor 1 Receptor)

• Figitumumab

• Cixutumumab

• Not found to be effective in soft tissue sarcomas

Targeting the PI3A-Akt-mTOR Pathway and IGF1R

Histone Deacetylase Inhibitors

• HDAC Inhibitors

• Panobinostat

• Vorinostat

• Good activity seen in pre clinical models of translocation related sarcomas (Synovial sarcoma, Ewing sarcoma)

• Disappointing results in clinical trials as single agent therapy or in combination with chemotherapy

Hedgehog and Notch Signaling

• Hedgehog and Notch pathways play important role in development of pluricellular organisms

• Hedgehog pathway regulates the expression of several target genes involved in tumorigenesis

• Notch signalling is involved in maintainance of undifferentiated state, cell fate decision and induction of terminal differentiation

• Notch signalling is involved in human tumors both as an oncogene and as a tumor suppressor

• Hedgehog pathway plays an important in Rhabdomyosarcoma and Osteosarcoma

• Hedgehog pathway and Notch signalling inhibitors may be used in synergy in sarcomas displaying activation of both subtypes

• GDC-0449 (Hedgehog inhibitor) Phase I/II trials showing

• RO4929097 (Notch signalling inhibitor) stable disease

Hedgehog and Notch Signaling

SUBTYPE-SPECIFIC APPROACHES

• Targeting Angiogenesis in Vascular Tumors

• Targeting Angiogenesis in Alveolar Soft-Part Sarcoma

• Targeting MDM2 and CDK4 in Liposarcoma

• mTOR Inhibition in Perivascular Epitheloid cell Tumors

Targeting Angiogenesis in Vascular Tumors

• Angiosarcoma

• Epitheloid Hemangioendothelioma

• Hemangiopericytoma/Solitary fibrous Tumor

• Sorafenib : ANGIONEXT study – Activity of Sorafenib in Solitary Fibrous Tumor and Epitheloid Hemangioendothelioma

• Bevacizumab : Activity seen in Angiosarcoma and Epitheloid Hemangioendothelioma

Targeting Angiogenesis in Alveolar Soft-Part Sarcoma

• Bevacizumab with Interferon alpha

• Sunitinib

• Cediranib

Targeting MDM2 and CDK4 in Liposarcoma

• Amplification of MDM2 is a diagnostic criterion for well and dedifferentiated Liposarcomas

• CDK4 amplification is seen in nearly 90% cases

• MDM2

• E3 ubiquitin ligase

• Binds to p53 and targets for degradation by proteasome

• CDK4

• Cyclin dependent kinase regulating G1-S transition in cell cycle

• RG7112

• Orally bioavailable inhibitor of MDM2-p53

• Good response on well to dediffentiated liposarcomas with studies showing Stable disease

• PD0332991

• Acts against CDK4/6

• Good progression free survival at 12 weeks (70%)

Targeting MDM2 and CDK4 in Liposarcoma

mTOR Inhibition on Perivascular Epitheloid Cell Tumors

• Rapalogues

• Sirolimus

• Temsirolimus

• Good responses observed

• However, responses are short lived and only in some patients

OTHER APPROACHES

• Alisertib

• Aurora kinase A inhibitor

• Modest anti tumor activity in solid tumors and some patients with soft tissue sarcomas and advanced uterine sarcomas

• Ipilimumab

• CTLA4 (cytotoxic T-Lymphocyte Antigen 4) targeting monoclonal antibody

• Dasatinib

• Activity against sarcoma cell lines

• Being tried in combination with Ipilimumab