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Personalized Therapy of Medulloblastomas
Medulloblastoma is a malignant tumor of the cerebellum usually diagnosed in chil-
dren at the median age of 5 years, but it may occur in young adults. Treatment is
surgery followed by radiation therapy and chemotherapy, which have serious short-
term and long-term adverse effects. Patients with recurrence after primary therapy
have a particularly poor prognosis. The hedgehog pathway, an embryonic signaling
cascade that regulates stem-cell and progenitor-cell differentiation, is involved in
the pathogenesis as medulloblastoma arises from these cells. PTCH1 is an inhibi-
tory cell-surface receptor that constitutively suppresses activation of the hedgehog
pathway by inhibiting smoothened homologue (SMO) − a transmembrane protein
that activates the downstream hedgehog signaling pathway. Hedgehog ligands bind
to and inactivate PTCH1, de-repressing SMO and promoting pathway activation.
Activation of hedgehog signaling, usually due to inactivating mutations of PTCH1,
has been shown in ~30 % of medulloblastomas in humans.
GDC-0449, an orally bioavailable selective inhibitor of SMO, showed effi cacy in
phase I trials on patients with advanced basal-cell carcinoma, another type of tumor
that is known to harbor PTCH1 mutations. It was used successfully in a patient with
advanced medulloblastoma that had been refractory to multiple prior therapies
(Rudin et al. 2009 ). However, this patient rapidly acquired resistance to GDC-0449.
Identifying the mechanisms of acquired resistance to selective hedgehog pathway
inhibitors in patients with medulloblastoma will be of particular interest in future
studies. The development of a diagnostic biomarker for hedgehog pathway activa-
tion has been challenging because alteration of many pathway components may
result in an activated phenotype. A gene-expression signature, which appears to
correlate with hedgehog pathway activation in medulloblastoma, showed specifi c
pathway activation in this patient’s tumor. Testing this and other potential strategies
for identifying biomarkers will be important components of future clinical trials of
hedgehog pathway inhibitors.
Personalized Management of Germ Cell Brain Tumors
A phase II study was carried to determine response to chemotherapy and survival
after response-based radiation therapy (RT) in children with CNS germ cell tumors
using serum or cerebrospinal fl uid (CSF) biomarkers: human chorionic gonadotro-
pin (HCG) and alpha-fetoprotein (AFP) (Kretschmar et al. 2007 ). Children with
germinomas and normal biomarkers received cisplatin + etoposide, alternating with
vincristine + cyclophosphamide (CPM) whereas children with nongerminomatous
tumors or with abnormal biomarkers received doubled doses of cisplatin and
CPM. For germinoma patients in complete response (CR), RT was decreased from
but dose was maintained in high-risk patients. Response (germinoma, 91 %; non-
germinomatous, 55 %) and survival are encouraging after this regimen plus
response-based RT.
10 Personalized Therapy of Cancer