Jiang, X; Hu, C; Ferchen, K; Nie, J; Cui, X; Chen, CH; Cheng, L; Zuo, Z; Seibel, W; Tang, Y; Skibbe, JR; Wunderlich, M; Reinhold, WC; Dong, L; Shen, C; Arnovitz, S; Ulrich, B; Lu, J; Weng, H; Su, R; Huang, H; Wang, Y; Qin, X; Mulloy, JC; Zheng, Y; Diao, J; Jin, J; Li, C; Liu, P; He, C; Chen, Y; Chen, J. Targeted inhibition of STAT/TET1 axis as a therapeutic strategy for acute myeloid leukemia. Nature Communications. 2017; 8(1).
Acute myeloid leukemia (AML) is a common leukemia in children and young adults. Development of new targeted therapies are few for AML, and outcomes are poor despite intensive chemotherapy. DNA methyl-cytosine dioxygenase Ten-eleven translocation 1 (TET1) is a critical oncoprotein in AML, particularly poor prognosis AML carrying t(11q23)/MLL- rearrangements. Through a series of data analysis and drug screening, we identified two novel compounds (i.e., NSC-311068 and NSC-370284) that selectively suppress TET1 transcription and 5- hydroxymethylcytosine (5hmC) modification, and effectively inhibit cell viability in AML with high expression of TET1 (i.e., TET1-high AML). These results provide the foundation for development of novel agents to target the STAT/TET1 axis in AML therapy.
Burns, KC; Hoefgen, H; Strine, A; Dasgupta, R. Fertility Preservation Options in Pediatric and Adolescent Patients With Cancer. Cancer. 2018; 124(9):1867-1876.
This review article highlights the growing importance of fertility preservation options in pediatric and AYA oncology. As childhood cancer survivorship rates continue to increase, the ability to mitigate late effects, including infertility, takes on greater importance. There have been significant advances in oncofertility, from tissue freezing techniques in the pre-pubertal patient to the establishment of comprehensive clinical teams dedicated to fertility preservation for at risk populations. Illustrated in this article is the multidisciplinary approach and underscores the importance of offering fertility counseling to all patients.
Drilon, A; Laetsch, TW; Kummar, S; DuBois, SG; Lassen, UN; Demetri, GD; Nathenson, M; Doebele, RC; Farago, A;F Pappo, AS; Turpin, B; Dowlati, A; Brose, MS; Mascarenhas, L; Federman, N; Berlin, J; El-Deiry, WS; Baik, C; Deeken, J; Boni, V; Nagasubramanian, R; Taylor, M; Rudzinski, ER; Meric-Bernstam, F; Sohal, DPS; Ma, PC; Raez, LE; Hechtman, JF; Benayed, R; Ladanyi, M; Tuch, BB; Ebata, K; Cruickshank, S; Ku, NC; Cox, MC; Hawkins, DS; Hong, DS; Hyman, DM. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. The New England journal of medicine. 2018; 378(8):731-739.
Next generation sequencing (NGS) of cancers in adults and children has significantly broadened the understanding of molecular drivers of cancer, and genomic alterations occasionally guide highly successful therapy choices. TRK fusions define a rare subgroup of cancers across multiple histologies and across a wide age range, often identified through NGS efforts. Loxo oncology partnered with both pediatric and adult institutions to rapidly and simultaneously identify and treat eligible patients with TRK fusion positive cancers. Fifty-five eligible patients with 17 unique tumor types received larotrecinib, a highly potent and specific oral pan-TRK inhibitor, and demonstrated an unprecedented response rate of 75% (71% of which were ongoing at 1 year, many complete responses), across all histology and age groups, with minimal side effects. This study demonstrates the ability of a highly effective phase I/II study to rapidly and simultaneously accrue both pediatric and adult patients with rare tumor types unified only by their genomic alteration, and serves as a model for future therapeutic trials.
Anderson, JL; Muraleedharan, R; Oatman, N; Klotter, A; Sengupta, S; Waclaw, RR; Wu, J; Drissi, R; Miles, L; Raabe, EH; Weirauch, ML; Fouladi, M; Chow, LM; Hoffman, L; DeWire, M; Dasgupta, B. The transcription factor Olig2 is important for the biology of diffuse intrinsic pontine gliomas. Neuro-Oncology. 2017; 19(8):1068-1078.
Diffuse intrinsic pontine glioma (DIPG) is a pediatric brain tumor with no cure. The identity of genes that drive pathogenicity of this lethal tumor is not well understood. Using patient-derive DIPG cell lines, we show the requirement of transcription factor Olig2 for tumor formation in an orthotopic mouse model of DIPG. Olig2 expression is heterogeneous but high in DIPG. We found that unidentified factors in fetal bovine serum suppress Olig2 in cultured DIPG cells making them incapable of tumor formation when transplanted to mice. On the contrary, cultured DIPG stem-like cells grown in serum-free medium forms robust tumors in mice blocked by genetic silencing of Olig2.
Banerjee, A; Jakacki, RI; Onar-Thomas, A; Wu, S; Nicolaides, T; Poussaint, T; Fangusaro, J; Phillips, J; Perry, A; Turner, D; Prados, M; Packer, RJ; Qaddoumi, I; Gururangan, S; Pollack, IF; Goldman, S; Doyle, LA; Stewart, CF; Boyett, JM; Kun, LE; Fouladi, M. A phase I trial of the MEK inhibitor selumetinib (AZD6244) in pediatric patients with recurrent or refractory low-grade glioma: a Pediatric Brain Tumor Consortium (PBTC) study. Neuro-Oncology. 2017; 19(8):1135-1144.
Low-grade gliomas (LGGs) are the most common form of childhood brain tumor, representing over 30% of CNS tumors. Activation of the mitogen-activated protein kinase pathway is important for growth of pediatric LGG, and is often related to BRAF oncogene alterations. This study showed that the mitogen-activated protein kinase pathway inhibitor, selumetinib, induces responses in 20% of pediatric LGG patients and particularly those with BRAF mutations. This work provides the foundation for molecular therapy of pediatric LGG.