2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

TARGETED THERAPY IN SARCOMA
seen in the patient without the translocation. Of note, a
F1174L point mutation was observed in the first patient,
who developed secondary resistance to crizotinib. This point
mutation was previously identified in neuroblastoma specimens
and demonstrated in vitro resistance to crizotinib but
sensitivity to TAE684, a chemically distinct ALK inhibitor
that has not yet been clinically tested in patients with
IMT. 43
Together, these genetic, pathologic, and limited clinical
findings demonstrate that a subset of IMT have activating
rearrangements of ALK, and provide preliminary evidence
that IMT patients with ALK rearrangements may derive
clinical benefit from ALK inhibitors. Further clinical experience
with ALK inhibitors in this disease will strengthen
the translation of these observations.
mTOR Activation in Perivascular Epithelioid
Cell Tumor
The perivascular epithelioid cell tumor (PEComa) family
consists of mesenchymal neoplasms with epithelioid morphology
and myomelanocytic differentiation. 44 These tumors
present as small pulmonary nodules with cystic lung
destruction in lymphangioleiomyomatosis (LAM), benign
renal masses with vascular, myogenic, and adipocytic differentiation
in angiomyolipoma (AML), or PEComa, an epithelioid
tumor with nests and sheets of cells with clear-togranular
eosinophilic cytoplasm arising most commonly in
the uterus, retroperitoneum, and somatic soft tissues. Although
LAM, AML, and PEComa may arise sporadically,
LAM and AML in particular are also found in patients with
tuberous sclerosis, an autosomal dominant syndrome caused
by inherited mutations in the TSC1 or TSC2 tumor suppressor
genes. Inactivation of the TSC1/2 complex leads to hyperactivation
of mTOR and dysregulated cellular proliferation.
An evaluation of the mTOR inhibitor sirolimus in patients
AML or LAM 45 showed modest reduction in size of AML and
improvement in lung function, supporting the mechanistic
role of mTOR activity in these diseases. On the basis of
the morphologic similarity of PEComa to AML and LAM,
biochemical evidence of enhanced mTOR activity in
PEComa, 46,47 and chromosomal abnormalities at the TSC1
or TSC2 loci, the effects of sirolimus was explored in three
consecutive patients with malignant PEComa. 48 All three
patients experienced clinical benefit, but with duration varying
from several months to several years. Retrospective
analysis of tumor specimens demonstrated loss of expression
of TSC2 in all tumors, but not in healthy tissues, and loss of
both copies of TSC1 in one tumor. These findings support
the use of mTOR inhibitors in this disease. Similar clinical
responses to mTOR inhibitors have been reported in other
case reports, 49,50 but not all patients have derived such
benefit. Further studies identifying predictive factors and
mediators of resistance are needed.
Hedgehog Signaling in Chondrosarcoma
Chondrosarcomas are malignant neoplasms that most
commonly arise in bone and have cartilaginous differentiation.
No effective systemic therapies have been described for
unresectable or metastatic disease. The hedgehog (HH)
signaling pathway is implicated in normal chondrocyte development
as well as in malignant transformation. Oncogenic
activation of the HH pathway can result from multiple
insults, including loss-of-function mutations in Patched (ligand)
that lead to constitutive activation of the receptor,
Smoothened (SMO) as well as dysregulated expression of
HH ligands leading to paracrine or autocrine tumor cell
stimulation.
Constitutively activated HH signaling has been identified
in chondrosarcoma tumors. 51 IPI-926, an orally available
SMO antagonist, has been evaluated on primary chondrosarcoma
xenograft model. 52 Treatment of established xenografts
with IPI-926 resulted in substantially smaller tumor
sizes compared with chemotherapy- or control-treated animals.
Consistent with HH pathway modulation, reduction in
expression of target genes was also observed in both the
tumor cells and the surrounding tumor-associated stroma.
These laboratory findings formed the basis of an ongoing
phase II study of IPI-926 compared with placebo in patients
with unresectable or metastatic chondrosarcoma.
Recently, mutations in the Krebs cycle enzymes isocitrate
dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2
(IDH2) have been identified in more than 50% of cartilaginous
tumors. 53 Similar mutations have been suggested to
confer an oncogenic neoactivity in gliomas and acute myelogenous
leukemia. Whereas the precise role of IDH1 and IDH2
mutations has yet to be described in chondrosarcoma behavior,
these, too, may present an opportunity for targeted
therapeutic approaches that can be explored when suitable
drugs are available for clinical study.
Conclusion
The examples described in this article validate the concept
that deeper understanding of the molecular mechanisms
associated with the development of sarcoma positively affects
patient outcomes. Until our understanding of individual
sarcoma subtypes evolves further, it is essential to
conduct clinical trials with biologic correlatives designed to
gain a better understanding of potential subtypes likely to
benefit from novel targeted therapies. The rarity and heterogeneity
of soft tissue and bone sarcoma necessitates that
our basic scientists and clinical colleagues continue collaboration
to bring observations from both preclinical and clinical
realms to the forefront to more rapidly provide effective
therapies to our patients.
655