Understanding the S45F and T41A mutations in desmoid tumors

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1 Understanding the S45F and mutations in desmoid tumors D Braggio PhD, R Pollock MD PhD, D Lev MD The Ohio State University James Cancer Center Columbus, Ohio Tel Aviv University Sheba Medical Center Tel Aviv, Israel

2 Desmoid key clinical features bone - Low-grade; locally invasive - Local recurrence common - Lack ability to metastasize desmoid 13 operations

3 Progress will require multidisciplinary/molecular approaches

4 In deciding where to begin, we invoked Sutton s law: who was Sutton?

5 -catenin is the most commonly overexpressed protein in desmoid fibromatosis Study n/total % Tejpar et al., / Abraham et al., /33 82 Montgomery et al., /10 90 Bhattacharya et al., / Ng et al., /17 82 Rakheja et al., /12 33

6 -catenin: a key component of the WNT pathway

7 -catenin: mediates cell-to-cell adhesion and signalling needed to form complex tissues

8 -catenin Widely expressed in many normal tissues Over-expression associated with many cancers (liver, colon, lung, breast, ovary) Over-expression in non-malignant diseases: cardiomyopathy, depression Regulated and destroyed (removed) by APC protein

9 CTNNB1 gene regulates -catenin production

10 Only three known mutations of CTNNB1, the gene underlying -catenin protein production/ over-production in desmoid 138 MDACC desmoid patients (JCO study); primary and recurrent tumors: 85% mutated 15% wild type

11 We asked if CTNNB1 mutational status correlated with desmoid recurrence

12 Desmoid prognosis: effect of 45F mutation Entire series (n=138 pts) Possible impact on clinical decision-making???

13 45 F mutation: strongest prognostic factor for recurrence

14 Confirming the role of CTNNB1 45F mutations British Jour Can, 102:1032; 2010 Cancer 119:3696; 2013 Ann Surg Onc, 22:1464; 2015

15 Exploring the biology underlying desmoid tumors: why are CTNNB1 S45F mutations bad news???

16 Desmoid cell strains isolated at MDA/OSU Confirmed as DT cells via CTNNB1 genotyping of cells and original tumors TUMOR CTNNB1 Des1 Des2 Des4 WT Des6 S45F Des7 Des8 WT Des9 Des10 Des11 S45F Des14 S45F Des18 S45F Des19A S45P Des20 Des24 Des27 Des38 WT Des39 Des40 S45F Des41 Des42 Des43 Des44 S45P Des45 Des50 Des51 Des39B Des26 Des46 Des47 H36P Des55 WT Des65 Des67 OSU-Des1 S45F OSU-Des16 S45F OSU-Des17 OSU-Des9 WT OSU-Des13 S45F OSU-Des23 S45F OSU-Des33 S45P OSU-Des34 OSU-Des44 OSU-Des47 S45P OSU-Des68 S34R OSU-Des78 OSU-Des23.2 S45F OSU-Des76 OSU-Des91 OSU-Des93 WT OSU-Des104 OSU-Des113 S45P OSU-Des119 OSU-Des101 OSU-Des128 S45P OSU-Des124, OSU-Des130 Created with DTRF support!

17 Apoptosis: programmed cell death; inducible by chemotherapy, radiation

18 Apoptotic genes are differentially expressed in S45F mut desmoid tumors Apoptosis-promoting genes Apoptosis-inhibiting genes ** ** N=27 N=27 ** = P > 0.001

19 Cleaved caspase (fold change) S45F mut DT cells: decreased apoptosis activation T41 A S45F S45F Time (h)

20 S45F mut DT cells: decreased apoptosis activation T41 A S45F P >0.001 **

21 Desmoid treatment: Dox-based chemotherapy Patel et al. Cancer; 1993

22 Contemporary systemic approaches to desmoid ASCO; 2015

23 No significant induction of apoptosis in S45F mut DT cells after doxirubicin treatment OSU-Des76 OSU-Des91 Des65 Des67 OSU-Des13 OSU-Des23 OSU-Des23.2 Des % 23.8% 4.9% 7.2% 5.1% 6.8% 6.2% 6.2% DMSO 41.6% 51.6% 16.6% 26.5% 5.6% 7.7% 10.1% 6.5% Doxorubicin (0.2mg/mL) T41 S45F

24 Therapeutic implications???

25 -catenin knockdown decreases desmoid growth--new windows for exploration? CTNNB1 sirna: Reduced protein Reduced proliferation Reduced migration Reduced invasion Ubiquity of -catenin precludes direct targeting

26 OSU randomized Phase II clinical trial (concept) Biopsy proven desmoid tumor DNA sequencing CTNNB1 pts with S45F mutation Randomization Arm 1: surgery alone Arm 2: pre-op RT followed by surgery or surgery followed by postop RT Primary endpoint: recurrence status at 36 months Investigative team: Meng Welliver (Radiation Oncology) Raphael Pollock (Surgical Oncology) Xiaokui Mo (Center for Biostatistics)

27 Although the pathway to progress in sarcoma is not always clear

28 The clarity we seek will come by working together!

29 So I m looking forward to our shared next steps!

30 My Desmoid Heroines Dina Lev, MD Danielle Braggio, PhD Support: Desmoid Tumor Research Foundation

31 Many thanks to our OSU sarcoma colleagues! Pathology Hans Iwenofu, MD Paul Wakely, MD Radiation Oncology Douglas Martin, MD Meng Welliver, MD, PhD Karl Haglund, MD Medical Oncology David Liebner, MD James Chen, MD, PhD Orthopedic Oncology Thomas Scharschmidt, MD Joel Mayerson, MD Neurosurgery Ehud Mendel, MD Surgical Oncology Harrison Howard, MD Valerie Grignol, MD Sarcoma Research Laboratory Gonzalo Lopez, PhD Kate Lynn Bill, PhD Lucia Casadei, PhD Danielle Braggio, PhD Abby Zewdu, BS Kara Batte, PhD Anne Strohecker, PhD Dina Lev, MD P & RS Ian Valerio, MD Jeffrey Janis, MD Nationwide Childrens Hospital Timothy Cripe, MD, PhD Ryan Roberts, MD, PhD

32 Thank you for your attention; questions or comments? Sunset over Lake Michigan at Beverly Shores, Indiana; 7/23/16