PI3-Kinase Signaling. Rational Incorporation of Novel Agents into Multimodality Therapy. PI3-kinase. PI3-kinase 5/2/2010

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1 Rational Incorporation of Novel Agents into Multimodality Therapy I3-Kinase Signaling EGF IRS1 I3K EGFR I2 I3 TEN Rictor GßL AKT RAS40 Survival Raptor GßL Daphne Haas-Kogan UCSF Annual Course April 30-May 2, 2010 p70s6k Cell growth 4EB1 Does the I3-kinase pathway play a role in low-grade gliomas? TEN Expression and KB Activity Correlate with Glioma I3-kinase 2.0 < =0.02 TEN Level KB Activity I3-kinase 0.0 N = GBM OA NL Brain 0 N = GBM OA NL Brain Ermoian et al.,

2 TEN promoter methylation Epigenetic modification whereby the 5 cytosine carbon is methylated by the enzyme DNA Methyltransferase (DNMT). Results in transcriptional repression. Grade 2, Grade 3, and Secondary GBMs Show TEN romoter Methylation Number Methylated (%) Number Not methylated (%) Non-tumor brain (n=13) 0 (0) 13 (100) Grade II oligoastrocytomas (n=15) Grade II astrocytomas (n=14) Grade II oligodendrogliomas (n=8) Grade III astrocytomas (n=19) 10 (66.7) 5 (33.3) 6 (42.9) 8 (57.1) 4 (50) 4 (50) 13 (68) 6 (32) Secondary GBM (n=11) 9 (82) 2 (18) De novo GBM (n=23) 2 (8.7) 21 (91.3) Differentiated astrocytes or precursor cells 53 mutation (>65%) DGF-A, DGFR overexpression (~60%) Low grade astrocytoma LOH 19q (~50%) prb alteration (~25%) TEN methylation (~50%) Anaplastic astrocytoma LOH 10q TEN mutation (5%) DGFR amplification (<10%) TEN methylation (~80%) Secondary glioblastoma Smith&Jenkins 2000 EGFR amplification (~40%) overexpression (~60%) MDM2 amplification (<10%) overexpression (~50%) p16 deletion (30-40%) LOH 10p and 10q prb alteration TEN mutation (~30-40%) rimary glioblastoma de novo TEN promoter methylation in low-grade gliomas: clinical significance Hypothesis: patients with low-grade gliomas with activation of the I3-kinase/ pathway will have worse clinical course. Retrospective study: examined the relationship between TEN promoter methylation and activation of the I3-kinase/ pathway and survival in patients with low-grade gliomas. 2

3 atient characteristics and Results TEN promoter methylation and overall survival TEN Methylation Variables Total Number of patients 43 Median age at diagnosis (range), years 37 (20-64) Median Karnofsky erformance Score (range) 80 (60-100) Female:male 22:21 : Astrocytoma 21 (49%) Oligodendroglioma 15 (35%) Oligoastrocytoma 7 (16%) TEN promoter methylation: YES 26 (60%) Survival robability TEN unmethylated TEN methylated log rank p=0.128 Overall Survival: Shorter survival in patients with TEN promoter methylation (p=0.128) Six-year survival: 93% for unmethylated group 79% for methylated group. TEN methylated: 7 of 26 died TEN unmethylated: 1 of 17 died. NO 17 (40%) Time to Death (years) I3-Kinase and TEN S6 kinase phosphorylation and overall survival -S6 Ser 240 (all pts) roliferation GFR Ras Glycogen synthesis I3K TSC1/TSC2 4EB1 o o o o KB/Akt rotein synthesis p70 S6K S6 nutrients TEN Survival Actin cytoskeleton/ migration Survival robability S6 Ser S6 Ser log rank p= % positive for phospho-s6 Median follow-up: 5.2 yrs for (+) phospho-s6 8.6 yrs for (-) phospho-s6 8 deaths all (+) phospho-s6 =0.029 Time to Death (years) 3

4 Rationale for everolilmus (RAD001) in LGGs Activation of the I3K/ pathway occurs frequently (at least 50%) in low-grade gliomas. Activation of the I3K/ pathway in low-grade gliomas may promote recurrences as secondary high-grade lesions, and therapies that target tumors with increased KB/Akt activity may be of clinical benefit in low-grade gliomas. reclinical and clinical studies indicate that tumors with increased I3K/Akt activity are particularly susceptible to agents that inhibit. hase II Trial of everolimus (RAD001) in Adults with Recurrent LGGs: Schema Recurrent LGG with histological evidence of progression/recurrence N=60 Enroll in hase II trial of RAD mg daily, orally, continuously MRI, clinical evaluation, QOL assessments every 2 months for one year MRI, clinical evaluation, QOL assessments every 3 months for two years rogression Off therapy Stable disease or response Continue RAD001 for up to 2 years hase II Trial of RAD001 (everolimus) in Adults with Recurrent LGGs: A single-arm, one-stage phase II trial of RAD001. atients with a diagnosis of low-grade glioma who experience a recurrence and who undergo a biopsy or subtotal resection at the time of recurrence with pathologic evidence of recurrent glioma. Test the hypothesis that tumors with activation of the I3K signaling cascade will preferentially respond to RAD001. hase II Trial of everolimus in Adult Recurrent LGGs: From March 16, 2009 to Jan 04, 2010 total of 11 patients enrolled Baseline Demographic and Disease characteristics Characteristic N=11 Age (years) Median Range Sex Male Female KS (at baseline) Median 90 Tumor Type (most recent surgery) Astrocytoma Oligodendroglioma Anaplastic Oligodendroglioma

5 hase II Trial of everolimus in Adult Recurrent LGGs: Of 11 patients enrolled, 8 patients are currently active on treatment, 1 patient withdrew, and 2 experienced tumor progression and were removed from protocol. One of the first patients to enroll in study: 42 years old woman with recurrent, grade 2 oligodendroglioma initially diagnosed in July 1997, treated with surgery and radiation. atient has experienced 4 progressions since then: First recurrence in 2005 treated with temozolomide Second recurrence in May 2008 treated with surgery Third recurrence in October 2008 treated with dose-dense temozolomide Fourth recurrence in June 2009 treated with surgery atient began treatment with everolimus on July 23, 2009 and complains only of mild fatigue hase II Trial of everolimus in Adult Recurrent LGGs: July 17, 2009: re-treatment with everolimus MRI FLAIR axial series. Nov. 10, 2009: Follow-up MRI FLAIR series continues to show decreased FLAIR abnormalities. LAB CLINIC LGG Hypothesis: Hypothesis tumors driven positive molecularly for I3K/ targeted activation therapies are more likely to respond to everolimus than tumors negative for these Capitalize on known aberrations and identify new targets molecular markers 5