Molecular and Genetic Features Across Mouse and Human Plexiform Neurofibromas to Inform Clinical Trials

  • D. Wade Clapp, MD Basic Science Co-Leader (Indiana University School of Medicine)

  • Jaishri Blakeley, MD Clinical Science Co-Leader (Johns Hopkins University)

  • Brigitte Widemann, MD Clinical Science Co-Leader (National Institutes of Health)

  • Lu Le, MD, PhD Basic Science Co-Leader (University of Texas, Southwestern)

  • Kent Robertson, MD, PhD Co-Investigator (Indiana University School of Medicine)

Description

Subsequent malignant neoplasms (SMNs) are histologically distinct cancers that develop months to years after patients receive radiation and/or chemotherapy to cure a primary malignancy. SMNs are a fundamental problem in cancer survivors. Compelling data generated by Drs. Nakamura and Shannon in GEM mice demonstrated that irradiation cooperates strongly with heterozygous Nf1 inactivation in the development of a spectrum of SMNs that recapitulate common SMNs in human patients with and without NF1. Project 4 will translate these novel data and will systematically assess the incidence of SMNs in NF1 patients and examine associated risk factors such as age at diagnosis, anatomic site of the primary tumor, and dose and duration of prior treatment. Data compiled by the NCI-funded Childhood Cancer Survivor Study (CCSS) will play an integral role in Project 4.

Aims

Aim 1:

Evaluate tumor and circulating markers before and after treatment with the MEK inhibitor selumetinib in pediatric and adult patients with NF1 associated plexiform neurofibromas.

Aim 2:

Evaluate the molecular adaptive responses, PK/PD and clinical response of plexiform neurofibromas in genetically engineered mice (GEM) with selumetinib alone, and in combination with imatinib mesylate.

Aim 3:

Utilize GEM models to identify the optimal therapeutic window(s) of c-kit (SCF) inhibition at distinct embryonic and adult stages of PN formation utilizing Nf1flox/- and Nf1flox/-;Scf flox/flox mice under the transcriptional control of a PLP tamoxifen + Cre transgene.

Translational Impact

The translational impact of this project involves: (1) defining therapeutic window(s) for c-kit inhibition at distinct embryonic and adult stages of PN formation; (2) investigating a rational approach to combinatorial therapy based on simultaneously interfering with paracrine growth signals emanating from the tumor microenvironment while also targeting aberrant Raf/MEK/ERK pathway activation in tumor cells; and (3) defining novel biomarkers by analyzing tumor specimens and blood obtained both prior to and after treatment.

Publications

Early administration of imatinib mesylate reduces plexiform neurofibroma tumor burden with durable results after drug discontinuation in a mouse model of neurofibromatosis type 1

Armstrong AE, Rhodes SD, Smith A, Chen S, Bessler W, Ferguson MJ, Jiang L, Li X, Yuan J, Yang X, Yang FC, Robertson KA, Ingram DA, Blakeley JO, Clapp DW.

Pediatr Blood Cancer. 2020 May 27:e28372. doi: 10.1002/pbc.28372.

https://www.ncbi.nlm.nih.gov/pubmed/32459399

Translating current basic research into future therapies for neurofibromatosis type 1

Brosseau JP, Liao CP, Le LQ.

Br J Cancer. 2020 May 22. doi: 10.1038/s41416-020-0903-x. Review.

https://www.ncbi.nlm.nih.gov/pubmed/32439933

Selumetinib in Children with Inoperable Plexiform Neurofibromas

Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, Weiss B, Kim A, Bornhorst M, Shah AC, Martin S, Roderick MC, Pichard DC, Carbonell A, Paul SM, Therrien J, Kapustina O, Heisey K, Clapp DW, Zhang C, Peer CJ, Figg WD, Smith M, Glod J, Blakeley JO, Steinberg SM, Venzon DJ, Doyle LA, Widemann BC.

N Engl J Med. 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18.

https://www.ncbi.nlm.nih.gov/pubmed/32187457

Heterozygous Tumor Suppressor Microenvironment in Cancer Development

Brosseau JP, Le LQ.

Trends Cancer. 2019 Sep;5(9):541-546. doi: 10.1016/j.trecan.2019.07.004. Epub 2019 Aug 15. Review.

https://www.ncbi.nlm.nih.gov/pubmed/31474359

Cdkn2a (Arf) loss drives NF1-associated atypical neurofibroma and malignant transformation

Rhodes SD, He Y, Smith A, Jiang L, Lu Q, Mund J, Li X, Bessler W, Qian S, Dyer W, Sandusky GE, Horvai AE, Armstrong AE, Clapp DW.

Hum Mol Genet. 2019 Aug 15;28(16):2752-2762. doi: 10.1093/hmg/ddz095.

https://www.ncbi.nlm.nih.gov/pubmed/31091306

Overcoming BET Inhibitor Resistance in Malignant Peripheral Nerve Sheath Tumors

Cooper JM, Patel AJ, Chen Z, Liao CP, Chen K, Mo J, Wang Y, Le LQ.

Clin Cancer Res. 2019 Jun 1;25(11):3404-3416. doi: 10.1158/1078-0432.CCR-18-2437. Epub 2019 Feb 22.

https://www.ncbi.nlm.nih.gov/pubmed/30796033

NF1 heterozygosity fosters de novo tumorigenesis but impairs malignant transformation

Brosseau JP, Liao CP, Wang Y, Ramani V, Vandergriff T, Lee M, Patel A, Ariizumi K, Le LQ.

Nat Commun. 2018 Nov 27;9(1):5014. doi: 10.1038/s41467-018-07452-y.

https://www.ncbi.nlm.nih.gov/pubmed/30479396

Contributions of inflammation and tumor microenvironment to neurofibroma tumorigenesis

Liao CP, Booker RC, Brosseau JP, Chen Z, Mo J, Tchegnon E, Wang Y, Clapp DW, Le LQ.

J Clin Invest. 2018 Jul 2;128(7):2848-2861. doi: 10.1172/JCI99424. Epub 2018 May 21.

https://www.ncbi.nlm.nih.gov/pubmed/29596064

Common Histologically Benign Tumors of the Brain

Strowd RE 3rd, Blakeley JO.

Continuum (Minneap Minn). 2017 Dec;23(6, Neuro-oncology):1680-1708. doi: 10.1212/CON.0000000000000541. Review.

https://www.ncbi.nlm.nih.gov/pubmed/29200117

Identification of hair shaft progenitors that create a niche for hair pigmentation

Liao CP, Booker RC, Morrison SJ, Le LQ.

Genes Dev. 2017 Apr 15;31(8):744-756. doi: 10.1101/gad.298703.117. Epub 2017 May 2.

https://www.ncbi.nlm.nih.gov/pubmed/28465357

Preclinical Evidence for the Use of Sunitinib Malate in the Treatment of Plexiform Neurofibromas

Ferguson MJ, Rhodes SD, Jiang L, Li X, Yuan J, Yang X, Zhang S, Vakili ST, Territo P, Hutchins G, Yang FC, Ingram DA, Clapp DW, Chen S.

Pediatr Blood Cancer. 2016 Feb;63(2):206-13. doi: 10.1002/pbc.25763. Epub 2015 Sep 16.

https://www.ncbi.nlm.nih.gov/pubmed/26375012

Humanized neurofibroma model from induced pluripotent stem cells delineates tumor pathogenesis and developmental origins

Mo J, Anastasaki C, Chen Z, Shipman T, Papke JB, Yin KY, Gutmann DH, Le LQ.

J Clin Invest. 2020 Oct 27;139807.doi: 10.1172/JCI139807. Online ahead of print.

https://pubmed.ncbi.nlm.nih.gov/33108355/

Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial

Fisher MJ, Shih Chie-Schin, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, Zhang C, Angus SP, Johnson GL, Packer RJ, Allen JC, Ullrich NJ, Goldman S, Gutmann DH, Plotkin SR, Rosser T, Robertson KA, Widemann BC, Smith AE, Bessler WK, He Y, Park SJ, Mund JA, Jiang L, Bijangi-Vishehsaraei K, Thomas Robinson C, Cutter GR, Korf BR, Neurofibromatosis Clinical Trials Consortium, Blakeley JO, Clapp DW.

Nature Medicine 2020 Apr 9;382(15):1430-1442. doi: 10.1056/NEJMoa1912735. Epub 2020 Mar 18.

https://pubmed.ncbi.nlm.nih.gov/33442015/

Human cutaneous neurofibroma matrisome revealed by single cell RNA sequencing

Brosseau, J.P., Sathe, A.A., Wang, Y., Nguyen, T., Glass, D.A., Xing, C., Le L.Q.

Acta Neuropathol. Commun. 2021 Jan 7;9(1):11. doi: 10.1186/s40478-020-01103-4.

https://pubmed.ncbi.nlm.nih.gov/33413690/

Genetic disruption of the small GTPase RAC1 prevents plexiform neurofibroma formation in mice with neurofibromatosis type 1

Mund JA, Park S, Smith AE, He Y, Jiang L, Hawley E, Roberson MJ, Mitchell DK, Abu-Sultanah M, Yuan J, Bessler WK, Sandusky G, Chen S, Zhang C, Rhodes SD, Clapp DW.

J Biol Chem. 2020 Jul 17;295(29):9948-9958. doi: 10.1074/jbc.RA119.010981. Epub 2020 May 29.

https://pubmed.ncbi.nlm.nih.gov/32471868/

Ketotifen Modulates Mast Cell Chemotaxis to Kit-Ligand, but Does Not Impact Mast Cell Numbers, Degranulation, or Tumor Behavior in Neurofibromas of Nf1-Deficient Mice

Burks CA, Rhodes SD, Bessler WK, Chen S, Smith A, Gehlhausen JR, Hawley ET, Jiang L, Li X, Yuan J, Lu Q, Jacobsen M, Sandusky GE, Jones DR, Clapp DW, Blakeley JO.

Mol Cancer Ther. 2019 Dec;18(12):2321-2330. doi: 10.1158/1535-7163.MCT-19-0123. Epub 2019 Sep 16.

https://pubmed.ncbi.nlm.nih.gov/31527226/

Targeted Therapies for Malignant Peripheral Nerve Sheath Tumors

  • Luis Parada, PhD Basic Science Co-Leader (Memorial Sloan Kettering Cancer Center)

  • Stephen X. Skapek, MD Clinical Science Co-Leader (University of Texas, Southwestern)

  • Ted Laetsch, MD Co-Investigator (University of Texas, Southwestern)

  • Noelle Williams, PhD Co-Investigator (University of Texas, Southwestern)

  • Xiankai Sun, PhD Co-Investigator (University of Texas, Southwestern)

  • Guiyang Hao, PhD Co-Investigator (University of Texas, Southwestern)

Description

Malignant peripheral nerve sheath tumors (MPNST) evolve from pre-existing plexiform neurofibromas, and we therefore hypothesize that these aggressive sarcomas continue to express some of the transcriptional programs present in the initiating fetal precursor population. This, in turn, might create novel synthetic lethal dependencies that can be exploited therapeutically. Indeed, Dr. Parada recently identified CXCR4 and CDK4/6 as key drivers of MPNST cell proliferation and tumor progression in GEM models. The major goals of Project 2 are to translate these provocative preclinical data and to harness functional imaging to develop better markers of early response in MPNST.

Aims

Aim 1:

To optimize CXCR4 and Cyclin D1-associated CDK4/6 inhibition in MPNST.

Aim 2:

To conduct pilot, “Phase 0” studies of GEM-guided, molecularly-targeted therapy in MPNST.

Aim 3:

Utilize GEM models to identify the optimal therapeutic window(s) of c-kit (SCF) inhibition at distinct embryonic and adult stages of PN formation utilizing Nf1flox/- and Nf1flox/-;Scf flox/flox mice under the transcriptional control of a PLP tamoxifen + Cre transgene.

Translational Impact

The translational impact of these studies encompasses the development of a biomarker profile to identify early markers of MPNST progression and evaluate efficacy of CXCR4 and CDK4/6 inhibitors in clinical trials.

Publications

Cell Lineage-Based Stratification for Glioblastoma

Wang Z, Sun D, Chen YJ, Xie X, Shi Y, Tabar V, Brennan CW, Bale TA, Jayewickreme CD, Laks DR, Alcantara Llaguno S, Parada LF.

Cancer Cell. 2020 Sep 14;38(3):366-379.e8. doi: 10.1016/j.ccell.2020.06.003. Epub 2020 Jul 9.

https://pubmed.ncbi.nlm.nih.gov/32649888/

Efficacy of MEK Inhibition in Juvenile Myelomonocytic Leukemia

  • Kevin Shannon, MD Basic Science Co-Leader (University of California, San Francisco)

  • Mignon Loh, MD Clinical Science Co-Leader (University of California, San Francisco)

  • Benjamin Braun, MD, PhD Co-Investigator (University of California, San Francisco)

  • Elliot Stieglitz, MD Co-Investigator (University of California, San Francisco)

Description

Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm (MPN) that responds poorly to chemotherapy. Hematopoietic stem cell transplantation (HSCT) cures ~50% of patients. Our studies of JMML specimens proved that NF1 functions as a tumor suppressor gene in hematopoietic cells, and provided the first direct evidence of deregulated Ras signaling in primary cancer cells from NF1 patients. These studies support the role of hyperactive Ras signaling in JMML pathogenesis, and our group and other researchers subsequently discovered mutations in NRAS, KRAS, PTPN11, and CBL in JMML patient specimens. Overall, >85% of JMML cases have mutations in one of these genes, including 15-20% with clinical NF1 or mutations in the NF1 gene. Despite the routine use of HSCT, up to 30% of JMML patients progress to acute myeloid leukemia (AML). Consistent with the molecular genetics of JMML, using the Mx1-Cre transgene to inactivate the conditional mutant Nf1flox allele generated by the Parada lab or to express oncogenic KrasG12D or NrasG12D in the hematopoietic compartment induces a JMML-like MPN in mice. Preclinical trials in these accurate GEM models revealed remarkable efficacy of MEK inhibitors. Importantly, however, this, treatment does not eradicate mutant bone marrow cells, but modulates their proliferation and differentiation in vivo. The overall goals of Project 3 are to translate these promising preclinical data in JMML patients though an innovative clinical trial that includes deep molecular analysis.

Aims

Aim 1:

To conduct a national phase II investigator-initiated trial of the MEK inhibitor trametinib in JMML and other refractory pediatric leukemias, and to interrogate molecular mechanisms of response and resistance. This trial will be executed in collaboration with the National Cancer Institute’s Cancer Therapy Evaluation Program (CTEP) and the Developmental Therapeutics Consortium (DVL) of the Children’s Oncology Group (COG).

Aim 2:

To use genetically accurate mouse models of MPN and acute myeloid leukemia (AML) characterized by Nf1 inactivation to investigate the efficacy and mechanisms of action of “second generation” therapies, and to functionally validate candidate mechanisms of drug resistance.

Translational Impact

The translational impact of these studies involves rigorously testing a novel therapeutic strategy for an aggressive pediatric cancer with deep molecular analysis of primary leukemia cells to ascertain mechanisms of response and resistance.

Publications

Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing

Chao AK, Meyer JA, Lee AG, Hecht A, Tarver T, Van Ziffle J, Koegel AK, Golden C, Braun BS, Sweet-Cordero EA, Smith CC, Dvorak CC, Loh ML, Stieglitz E.

Leukemia. 2020 Feb;34(2):662-666. doi: 10.1038/s41375-019-0549-y. Epub 2019 Sep 12.

https://www.ncbi.nlm.nih.gov/pubmed/31511612

Molecular assessment of pretransplant chemotherapy in the treatment of juvenile myelomonocytic leukemia

Hecht A, Meyer J, Chehab FF, White KL, Magruder K, Dvorak CC, Loh ML, Stieglitz E.

Pediatr Blood Cancer. 2019 Nov;66(11):e27948. doi: 10.1002/pbc.27948. Epub 2019 Jul 26.

https://www.ncbi.nlm.nih.gov/pubmed/31347788

Disease burden and conditioning regimens in ASCT1221, a randomized phase II trial in children with juvenile myelomonocytic leukemia: A Children's Oncology Group study

Dvorak CC, Satwani P, Stieglitz E, Cairo MS, Dang H, Pei Q, Gao Y, Wall D, Mazor T, Olshen AB, Parker JS, Kahwash S, Hirsch B, Raimondi S, Patel N, Skeens M, Cooper T, Mehta PA, Grupp SA, Loh ML.

Pediatr Blood Cancer. 2018 Jul;65(7):e27034. doi: 10.1002/pbc.27034. Epub 2018 Mar 12.

https://www.ncbi.nlm.nih.gov/pubmed/29528181

Genome-wide DNA methylation is predictive of outcome in juvenile myelomonocytic leukemia

Stieglitz E, Mazor T, Olshen AB, Geng H, Gelston LC, Akutagawa J, Lipka DB, Plass C, Flotho C, Chehab FF, Braun BS, Costello JF, Loh ML.

Nat Commun. 2017 Dec 19;8(1):2127. doi: 10.1038/s41467-017-02178-9.

https://www.ncbi.nlm.nih.gov/pubmed/29259179

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML

Yoshimi A, Balasis ME, Vedder A, Feldman K, Ma Y, Zhang H, Lee SC, Letson C, Niyongere S, Lu SX, Ball M, Taylor J, Zhang Q, Zhao Y, Youssef S, Chung YR, Zhang XJ, Durham BH, Yang W, List AF, Loh ML, Klimek V, Berger MF, Stieglitz E, Padron E, Abdel-Wahab O.

Blood. 2017 Jul 27;130(4):397-407. doi: 10.1182/blood-2017-01-763219. Epub 2017 Jun 2. Erratum in: Blood. 2017 Sep 28;130(13):1602.

https://www.ncbi.nlm.nih.gov/pubmed/28576879

International Consensus Definition of DNA Methylation Subgroups in Juvenile Myelomonocytic Leukemia

Schönung M, Meyer J, Nöllke P, Olshen AB, Hartmann M, Murakami N, Wakamatsu M, Okuno Y, Plass C, Loh ML, Niemeyer CM, Muramatsu H, Flotho C, Stieglitz E, Lipka DB.

Clin Cancer Res. 2020 Nov 2.doi: 10.1158/1078-0432.CCR-20-3184.

https://pubmed.ncbi.nlm.nih.gov/33139265/

Molecular and phenotypic diversity of CBL-mutated juvenile myelomonocytic leukemia

Hecht A, Meyer JA, Behnert A, Wong E, Chehab F, Olshen A, Hechmer A, Aftandilian C, Bhat R, Choi SW, Chonat S, Farrar JE, Fluchel M, Frangoul H, Han JH, Kolb EA, Kuo DJ, MacMillan ML, Maese L, Maloney KW, Narendran A, Oshrine B, Schultz KR, Sulis ML, Van Mater D, Tasian SK, Hofmann W, Loh ML, Stieglitz E.

Hematologica 2020 Dec 30;Online ahead of print. doi: 10.3324/haematol.2020.270595.

https://pubmed.ncbi.nlm.nih.gov/33375775/

Targeting the Ras pathway in pediatric hematologic malignancies

Pikman Y, Stieglitz E.

Current Opinions in Pediatrics 2021 Feb 1;33(1):49-58. doi: 10.1097/MOP.0000000000000981. Epub 2020 Dec 29.

https://pubmed.ncbi.nlm.nih.gov/33394740/

KrasP34R and KrasT58I mutations induce distinct RASopathy phenotypes in mice

Wong JC, Perez-Mancera PA, Huang TQ, Kim J, Grego-Bessa J, Del Pilar Alzamora M, Kogan SC, Sharir A, Keefe SH, Morales CE, Schanze D, Castel P, Hirose K, Huang GN, Zenker M, Sheppard D, Klein OD, Tuveson DA, Braun BS, Shannon K.

JCI Insight. 2020 Nov 5;5(21):e140495.doi: 10.1172/jci.insight.140495.

https://pubmed.ncbi.nlm.nih.gov/32990679/

Genetic disruption of N-RasG12D palmitoylation perturbs hematopoiesis and prevents myeloid transformation in mice

Zambetti NA, Firestone AJ, Remsberg JR, Huang BJ, Wong JC, Long AM, Predovic M, Suciu RM, Inguva A, Kogan SC, Haigis KM, Cravatt BF, Shannon K.

Blood. 2020 May 14;135(20):1772-1782. doi: 10.1182/blood.2019003530.

https://pubmed.ncbi.nlm.nih.gov/32219446/

Secondary Cancers among NF1 Cancer Survivors Outcome

  • Smita Bhatia, MD Clinical Science Co-Leader (University of Alabama, Birmingham)

  • Jean L. Nakamura, MD Basic Science Co-Leader (University of California, San Francisco)

  • Michael Fisher, MD Co-Investigator (Children’s Hospital of Philadelphia)

  • Lennie Wong, PhD Co-Investigator (City of Hope)

Description

Subsequent malignant neoplasms (SMNs) are histologically distinct cancers that develop months to years after patients receive radiation and/or chemotherapy to cure a primary malignancy. SMNs are a fundamental problem in cancer survivors. Compelling data generated by Drs. Nakamura and Shannon in GEM mice demonstrated that irradiation cooperates strongly with heterozygous Nf1 inactivation in the development of a spectrum of SMNs that recapitulate common SMNs in human patients with and without NF1. Project 4 will translate these novel data and will systematically assess the incidence of SMNs in NF1 patients and examine associated risk factors such as age at diagnosis, anatomic site of the primary tumor, and dose and duration of prior treatment. Data compiled by the NCI-funded Childhood Cancer Survivor Study (CCSS) will play an integral role in Project 4.

Aims

Aim 1:

To describe the magnitude of risk of second malignant neoplasms (SMNs) in individuals with NF1.

Aim 2:

To perform comparative oncogenomics to identify genetic alterations associated with radiation-induced tumorigenesis in individuals with NF1.

Aim 3:

To validate in model systems the biologic importance of candidate pathways in radiation-induced tumorigenesis and to determine whether radiotherapy promotes transformation of plexiform neurofibromas to MPNSTs in vivo.

Translational Impact

The translational impact of this work involves informing current clinical practice in the treatment of tumors arising in NF1 patients to reduce the risk of SMN, and generating insights into the underlying biology of SMN that will lead to new therapies for these common, aggressive, and largely refractory cancers.

Subsequent Neoplasms After a Primary Tumor in Individuals With Neurofibromatosis Type 1

Bhatia S, Chen Y, Wong FL, Hageman L, Smith K, Korf B, Cannon A, Leidy DJ, Paz A, Andress JE, Friedman GK, Metrock K, Neglia JP, Arnold M, Turcotte LM, de Blank P, Leisenring W, Armstrong GT, Robison LL, Clapp DW, Shannon K, Nakamura JL, Fisher MJ.

J Clin Oncol. 2019 Nov 10;37(32):3050-3058. doi: 10.1200/JCO.19.00114. Epub 2019 Sep 18.

https://www.ncbi.nlm.nih.gov/pubmed/31532722

A high-throughput screen of real-time ATP levels in individual cells reveals mechanisms of energy failure

Mendelsohn BA, Bennett NK, Darch MA, Yu K, Nguyen MK, Pucciarelli D, Nelson M, Horlbeck MA, Gilbert LA, Hyun W, Kampmann M, Nakamura JL, Nakamura K.

PLoS Biol. 2018 Aug 27;16(8):e2004624. doi: 10.1371/journal.pbio.2004624. eCollection 2018 Aug.

https://www.ncbi.nlm.nih.gov/pubmed/30148842

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies

Davidson PR, Sherborne AL, Taylor B, Nakamura AO, Nakamura JL.

Sci Rep. 2017 Aug 9;7(1):7645. doi: 10.1038/s41598-017-07888-0.

https://www.ncbi.nlm.nih.gov/pubmed/28794481

Somatic and Germline TP53 Alterations in Second Malignant Neoplasms from Pediatric Cancer Survivors

Sherborne AL, Lavergne V, Yu K, Lee L, Davidson PR, Mazor T, Smirnoff IV, Horvai AE, Loh M, DuBois SG, Goldsby RE, Neglia JP, Hammond S, Robison LL, Wustrack R, Costello JF, Nakamura AO, Shannon KM, Bhatia S, Nakamura JL.

Clin Cancer Res. 2017 Apr 1;23(7):1852-1861. doi: 10.1158/1078-0432.CCR-16-0610. Epub 2016 Sep 28.

https://www.ncbi.nlm.nih.gov/pubmed/27683180

Nf1 mutant tumors undergo transcriptome and kinome re-modeling after inhibition of either mTOR or MEK

Pucciarelli D, Angus SP, Huang B, Zhang C, Nakaoka HJ, Krishnamurthi G, Bandyopadhyay S, Clapp DW, Shannon K, Johnson GL, Nakamura JL.

Mol Cancer Ther. 2020 Aug 26;1017.2019. doi: 10.1158/1535-7163.MCT-19-1017.

https://pubmed.ncbi.nlm.nih.gov/32847978/

Defining the ATPome reveals cross-optimization of metabolic pathways

Bennett NK, Nguyen MK, Darch MA, Nakaoka HJ, Cousineau D, Ten Hoeve J, Graeber TG, Schuelke M, Maltepe E, Kampmann M, Mendelsohn BA, Nakamura JL, Nakamura K.

Nat Commun. 2020 Aug 28;11(1):4319. doi: 10.1038/s41467-020-18084-6.

https://pubmed.ncbi.nlm.nih.gov/32859923/

Germline MUTYH Mutation in a Pediatric Cancer Survivor Developing a Secondary Malignancy

avergne V, Sabnis A, Tupule A, Davidson PR, Kline C, Matthay K, Nicolaides T, Goldsby R, Braunstein S, Fogh SE, Sneed PK, Menzel P, Nakamura A, DuBois SG, Haas-Kogan DA, Nakamura JL.

Pediatr Hematol Oncol 2020 Oct;42(7):e647-e654. doi: 10.1097/MPH.0000000000001668.

https://pubmed.ncbi.nlm.nih.gov/31815884/