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Vismodegib in an adult patient with medulloblastoma

Agosto 2013

A 32 years old female patient presented in 2006 to the emergency room of The Fundación Santa Fe de Bogotá with headaches, vertical diplopia and unsteady gait which gradually developped. CT revealed an intra-axial cerebellar mass measuring 40x40 mm affecting the vermis. She underwent gross total resection with frozen section compatible with a primitive neuroectodermical pattern. Final report was consistent with a desmoplastic nodular medulloblastoma (WHO grade IV), Ki67 of 20%, focal reactivity for synaptophysin, neurofilament and CD99. Bone marrow biopsy and cerebrospinal fluid were negative. She received adjuvant craniospinal radiotherapy followed by chemotherapy with cyclophosphamide, cisplatin, etoposide and vincristine. She was then closely followed with no evidence of relapse until 5 years later when an MRI identified a new lesion within the posterior fossa which was biopsied and confirmed recurrent disease. She was evaluated altogether with the oncology department at MD Anderson Cancer Center (MDACC), deciding to treat with induction chemotherapy with cyclophosphamide, cisplatin and etoposide. She was then given a dose intensive regimen carboplatin, thiotepa and etoposide) followed by an autologous stem cell transplantation with transient and acceptable toxicity. After 11-month follow-up she developed some gait disturbances related to MRI changes indicating focal tumor relapse treated with gamma knife. Three months after that the patient underwent to a new image control that showed leptomeningeal infiltration (Figure. 1). In parallel she tested positive for SHH and Patched-1 activation by inmunohistochemistry, determining in agreement with MDACC switch to vismodegib 150 mg/day. After two months of treatment, MRI showed a maximum partial response (Figure. 2). Symptoms improved, and neurological exam was consistent with significant clinical improvement as well, and no significant toxicity.

Medulloblastomas (MB) are primary malignant embryonal tumours of the central nervous system (CNS). They are the most common CNS tumor in pediatric population, but are rare in the adult population, with a reported incidence of 0.5 per million, accounting for less than 1% of primary brain tumors in young adults.1 Clinical features include truncal ataxia, gait disturbances and symptoms derived of increased intracraneal pressure (headaches, vomiting). The majority originate within the posterior fossa, sometimes infiltrating across the ependymal lining into the brainstem or disseminate within central spinal fluid. Most of the information regarding its treatment is extrapolated from pediatric data or based on retrospective reviews. Patients with recurrent disease after primary therapy have a particularly por prognosis, with a median survival of less than 6 months, with a 2-year survival rate of approximately 9%2. Second line therapy is limited. Wide-genomic sequencing identified four distinct molecular subtypes: WNT, SHH, group 3 and group 4. Sonic Hedhehog (SHH) is the most common, accounting for 60 to 80% of all adult MB. These medulloblastomas are often desmoplastic.3

Hedgehog pathway is an embryonc signaling cascade that regulates stem cell differentiation, activated by transmembrane protein smoothened homologue (SMO). PTCH1, Sonic Hedgehog receptor, suppreses activation of the hedgehog pathway by inhibiting SMO. SHH binding to PTCH1 results in inactivation of PTCH1, limiting SMO inhibition and promoting pathway activation2,4,5. Thereby, mutations resulting in overactivation of SHH are critical in the pathogenesis of various malignancies including MB,  providing an opportunity for targeted therapy. First agent discovered as able of disrupting this pathway by binding to SMO was cyclopamine (Veratrum alkaloid)6,7, demonstrating in vitro and in vivo inhibition of tumor growth.This triggered active research to develop other SMO inhibitors. First results in human demonstrating a response to SMO inhibitor (GDC-0449) were published in 2009: phase I clinical trial reported an acceptable safety profile and encouraging anti-tumor activity in advanced basal cell carcinoma (BCC) and MB8. Rapid regression of the tumor was seen in metastatic MB2. These trials culminated with recent the approval of Vismodegib for Basal Cell Carcinoma (BCC) on January 2012. Although trials are still ongoing, SMO inhibitors are promising in MB. Results of phase II trial evaluating efficacy and safety of vismodegib in adult patients with recurrent or refractory MB medulloblastoma were presented recently. 32 patients with measureable disease were treated with vismodegib. No response was observed in non-SHH tumors. Three out of twenty patients with SHH tumors had a sustained response (mantained for at least 8 weeks).  Median duration of therapy of 2.76 months. Some patients remained on treatment for up to 13 months. Most common toxicity was grade 3 decrease in lymphocites, mialgia, seizures, back pain and syncope, presented by a total of 4 patients during first course and 3 patients during second. One patient experienced grade 4 thromboembolic event. These results demonstrated activity and security of vismodegib against recurrent or refractory SHH subtype medulloblastoma.9 And there are now at least 7 additional SMO antagonists in development, at various stages of clinical trial10.

agosto 2013 2

Figure 2. MRI post-treatment with vismodegib A. FLAIR; B. FLAIR; C. DWI; D. DWI; E. T1W contrast; F. T1W contrast. Axial views show disappearance of areas of enhancement identified in previous MRI.

Referencias
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2.Rudin CM. Treatment of medulloblastoma with hedgehog pathway inhibitor GDC-0449. N Eng J Med. 2009;361:1173-89.
3.Shonka N, Brandes A, De Groot JF. Adult medulloblastoma, from spongioblastoma cerebelli to the present day: a review of treatment and the integration of molecular markers. Oncology (Williston Park). 2013;26:1083-91.
4.Atwood SX, Chang ALS, Oro AE. Hedgehog pathway inhibition and the race against tumor evolution. J Cell Biol. 2012;199:193-7.
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6.Ruch JM, Kim EJ. Hedgehog signaling pathway and cancer therapeutics: progress to date. Drugs. 2013;73:613-23.
7.Chen JK, Taipale J, Cooper MK, Beachy P. a Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Develop. 2002;16:2743-8.
8.Lo Russo PM. Phase I trial of hedgehog pathway inhibitor vismodegib (GDC-0449) in patients with refractory, locally advanced or metastatic solid tumors. Clin Cancer Res. 2011;17:2502-11. (
9.Gajjar AJ, Amar J. A prospective phase II study to determine the efficacy of GDC 0449 (vismodegib) in adults with recurrent medulloblastoma (MB): A Pediatric Brain Tumor Consortium study (PBTC 25B). J Clin Oncol. 2013; abstr 2035.
10.Weiss GJ, Korn RL. Metastatic basal cell carcinoma in the era of hedgehog signaling pathway inhibitors. Cancer. 2012;118:5310-9.

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