Yong Yean Kim

All Publications

• KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma. Nature communications Kim, Y. Y., Gryder, B. E., Sinniah, R., Peach, M. L., Shern, J. F., Abdelmaksoud, A., Pomella, S., Woldemichael, G. M., Stanton, B. Z., Milewski, D., Barchi, J. J., Schneekloth, J. S., Chari, R., Kowalczyk, J. T., Shenoy, S. R., Evans, J. R., Song, Y. K., Wang, C., Wen, X., Chou, H. C., Gangalapudi, V., Esposito, D., Jones, J., Procter, L., O'Neill, M., Jenkins, L. M., Tarasova, N. I., Wei, J. S., McMahon, J. B., O'Keefe, B. R., Hawley, R. G., Khan, J. 2024; 15 (1): 1703

  Abstract

  Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.

  View details for DOI 10.1038/s41467-024-45902-y

  View details for PubMedID 38402212

  View details for PubMedCentralID PMC10894237

• CAR T-cells targeting FGFR4 and CD276 simultaneously show potent antitumor effect against childhood rhabdomyosarcoma. Nature communications Tian, M., Wei, J. S., Cheuk, A. T., Milewski, D., Zhang, Z., Kim, Y. Y., Chou, H. C., Liu, C., Badr, S., Pope, E. G., Rahmy, A., Wu, J. T., Kelly, M. C., Wen, X., Khan, J. 2024; 15 (1): 6222

  Abstract

  Chimeric antigen receptor (CAR) T-cells targeting Fibroblast Growth Factor Receptor 4 (FGFR4), a highly expressed surface tyrosine receptor in rhabdomyosarcoma (RMS), are already in the clinical phase of development, but tumour heterogeneity and suboptimal activation might hamper their potency. Here we report an optimization strategy of the co-stimulatory and targeting properties of a FGFR4 CAR. We replace the CD8 hinge and transmembrane domain and the 4-1BB co-stimulatory domain with those of CD28. The resulting CARs display enhanced anti-tumor activity in several RMS xenograft models except for an aggressive tumour cell line, RMS559. By searching for a direct target of the RMS core-regulatory transcription factor MYOD1, we identify another surface protein, CD276, as a potential target. Bicistronic CARs (BiCisCAR) targeting both FGFR4 and CD276, containing two distinct co-stimulatory domains, have superior prolonged persistent and invigorated anti-tumor activities compared to the optimized FGFR4-specific CAR and the other BiCisCAR with the same 4-1BB co-stimulatory domain. Our study thus lays down the proof-of-principle for a CAR T-cell therapy targeting both FGFR4 and CD276 in RMS.

  View details for DOI 10.1038/s41467-024-50251-x

  View details for PubMedID 39043633

  View details for PubMedCentralID PMC11266617

• Neopetrotaurines A-C, Isoquinoline Alkaloids with an Unprecedented Taurine Bridge from the Sponge Neopetrosia sp. Journal of natural products Wang, D., Jiang, W., Churiwal, M., Jia, K., Senadeera, S. P., Bokesch, H. R., Woldemichael, G. M., Kim, Y., Hawley, R. G., Wei, J. S., Khan, J., O'Keefe, B. R., Beutler, J. A., Gustafson, K. R. 2024; 87 (2): 332-339

  Abstract

  Neopetrotaurines A-C (1-3), unusual alkaloids possessing two isoquinoline-derived moieties that are linked via a unique taurine bridge, were isolated from a Neopetrosia sp. marine sponge. These new compounds have proton-deficient structural scaffolds that are difficult to unambiguously assign using only conventional 2- and 3-bond 1H-13C and 1H-15N heteronuclear correlation data. Thus, the application of LR-HSQMBC and HMBC NMR experiments optimized to detect 4- and 5-bond long-range 1H-13C heteronuclear correlations facilitated the structure elucidation of these unusual taurine-bridged marine metabolites. Neopetrotaurines A-C (1-3) showed significant inhibition of transcription driven by the oncogenic fusion protein PAX3-FOXO1, which is associated with alveolar rhabdomyosarcoma, and cytotoxic activity against PAX3-FOXO1-positive cell lines.

  View details for DOI 10.1021/acs.jnatprod.3c01041

  View details for PubMedID 38294825

• Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma. Cell reports. Medicine Tian, M., Wei, J. S., Shivaprasad, N., Highfill, S. L., Gryder, B. E., Milewski, D., Brown, G. T., Moses, L., Song, H., Wu, J. T., Azorsa, P., Kumar, J., Schneider, D., Chou, H. C., Song, Y. K., Rahmy, A., Masih, K. E., Kim, Y. Y., Belyea, B., Linardic, C. M., Dropulic, B., Sullivan, P. M., Sorensen, P. H., Dimitrov, D. S., Maris, J. M., Mackall, C. L., Orentas, R. J., Cheuk, A. T., Khan, J. 2023: 101212

  Abstract

  Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS. The 3A11 CAR T cells induced robust cytokine production and cytotoxicity against RMS cell lines in vitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR T cells, confirming the selectivity of 3A11 CAR T cells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR T cells are persistent in vivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR T cell therapy targeting FGFR4 to treat patients with RMS.

  View details for DOI 10.1016/j.xcrm.2023.101212

  View details for PubMedID 37774704

• A stem cell epigenome is associated with primary nonresponse to CD19 CAR T cells in pediatric acute lymphoblastic leukemia. Blood advances Masih, K. E., Gardner, R. A., Chou, H. C., Abdelmaksoud, A., Song, Y. K., Mariani, L., Gangalapudi, V., Gryder, B. E., Wilson, A. L., Adebola, S. O., Stanton, B. Z., Wang, C., Milewski, D., Kim, Y. Y., Tian, M., Cheuk, A. T., Wen, X., Zhang, Y., Altan-Bonnet, G., Kelly, M. C., Wei, J. S., Bulyk, M. L., Jensen, M. C., Orentas, R. J., Khan, J. 2023; 7 (15): 4218-4232

  Abstract

  CD19 chimeric antigen receptor T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary nonresponse (PNR), sustained CD19+ disease, and concurrent expansion of CD19-CAR occur in 20% of the patients and is associated with adverse outcomes. Although some failures may be attributable to CD19 loss, mechanisms of CD19-independent, leukemia-intrinsic resistance to CD19-CAR remain poorly understood. We hypothesize that PNR leukemias are distinct compared with primary sensitive (PS) leukemias and that these differences are present before treatment. We used a multiomic approach to investigate this in 14 patients (7 with PNR and 7 with PS) enrolled in the PLAT-02 trial at Seattle Children's Hospital. Long-read PacBio sequencing helped identify 1 PNR in which 47% of CD19 transcripts had exon 2 skipping, but other samples lacked CD19 transcript abnormalities. Epigenetic profiling discovered DNA hypermethylation at genes targeted by polycomb repressive complex 2 (PRC2) in embryonic stem cells. Similarly, assays of transposase-accessible chromatin-sequencing revealed reduced accessibility at these PRC2 target genes, with a gain in accessibility of regions characteristic of hematopoietic stem cells and multilineage progenitors in PNR. Single-cell RNA sequencing and cytometry by time of flight analyses identified leukemic subpopulations expressing multilineage markers and decreased antigen presentation in PNR. We thus describe the association of a stem cell epigenome with primary resistance to CD19-CAR therapy. Future trials incorporating these biomarkers, with the addition of multispecific CAR T cells targeting against leukemic stem cell or myeloid antigens, and/or combined epigenetic therapy to disrupt this distinct stem cell epigenome may improve outcomes of patients with B-ALL.

  View details for DOI 10.1182/bloodadvances.2022008977

  View details for PubMedID 36607839

  View details for PubMedCentralID PMC10440404

• An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma. The Journal of clinical investigation Tian, M., Cheuk, A. T., Wei, J. S., Abdelmaksoud, A., Chou, H. C., Milewski, D., Kelly, M. C., Song, Y. K., Dower, C. M., Li, N., Qin, H., Kim, Y. Y., Wu, J. T., Wen, X., Benzaoui, M., Masih, K. E., Wu, X., Zhang, Z., Badr, S., Taylor, N., Croix, B. S., Ho, M., Khan, J. 2022; 132 (16)

  Abstract

  Chimeric antigen receptor (CAR) T cell therapies targeting single antigens have performed poorly in clinical trials for solid tumors due to heterogenous expression of tumor-associated antigens (TAAs), limited T cell persistence, and T cell exhaustion. Here, we aimed to identify optimal CARs against glypican 2 (GPC2) or CD276 (B7-H3), which were highly but heterogeneously expressed in neuroblastoma (NB), a lethal extracranial solid tumor of childhood. First, we examined CAR T cell expansion in the presence of targets by digital droplet PCR. Next, using pooled competitive optimization of CAR by cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq), termed P-COCC, we simultaneously analyzed protein and transcriptome expression of CAR T cells to identify high-activity CARs. Finally, we performed cytotoxicity assays to identify the most effective CAR against each target and combined the CARs into a bicistronic "OR" CAR (BiCisCAR). BiCisCAR T cells effectively eliminated tumor cells expressing GPC2 or CD276. Furthermore, the BiCisCAR T cells demonstrated prolonged persistence and resistance to exhaustion when compared with CARs targeting a single antigen. This study illustrated that targeting multiple TAAs with BiCisCAR may overcome heterogenous expression of target antigens in solid tumors and identified a potent, clinically relevant CAR against NB. Moreover, our multimodal approach integrating competitive expansion, P-COCC, and cytotoxicity assays is an effective strategy to identify potent CARs among a pool of candidates.

  View details for DOI 10.1172/JCI155621

  View details for PubMedID 35852863

  View details for PubMedCentralID PMC9374382

• Lysine Demethylase 5A is Required for MYC Driven Transcription in Multiple Myeloma. Blood cancer discovery Ohguchi, H., Park, P. M., Wang, T., Gryder, B. E., Ogiya, D., Kurata, K., Zhang, X., Li, D., Pei, C., Masuda, T., Johansson, C., Wimalasena, V. K., Kim, Y., Hino, S., Usuki, S., Kawano, Y., Samur, M. K., Tai, Y. T., Munshi, N. C., Matsuoka, M., Ohtsuki, S., Nakao, M., Minami, T., Lauberth, S., Khan, J., Oppermann, U., Durbin, A. D., Anderson, K. C., Hideshima, T., Qi, J. 2021; 2 (4): 370-387

  Abstract

  Lysine demethylase 5A (KDM5A) is a negative regulator of histone H3K4 trimethylation, a histone mark associated with activate gene transcription. We identify that KDM5A interacts with the P-TEFb complex and cooperates with MYC to control MYC targeted genes in multiple myeloma (MM) cells. We develop a cell-permeable and selective KDM5 inhibitor, JQKD82, that increases histone H3K4me3 but paradoxically inhibits downstream MYC-driven transcriptional output in vitro and in vivo. Using genetic ablation together with our inhibitor, we establish that KDM5A supports MYC target gene transcription independent of MYC itself, by supporting TFIIH (CDK7)- and P-TEFb (CDK9)-mediated phosphorylation of RNAPII. These data identify KDM5A as a unique vulnerability in MM functioning through regulation of MYC-target gene transcription, and establish JQKD82 as a tool compound to block KDM5A function as a potential therapeutic strategy for MM.

  View details for DOI 10.1158/2643-3230.BCD-20-0108

  View details for PubMedID 34258103

  View details for PubMedCentralID PMC8265280

• Primary pulmonary artery sarcoma in the pediatric patient: Review of literature and a case report. Radiology case reports Kim, Y. Y., Wynn, T. T., Reith, J. D., Slayton, W. B., Lagmay, J., Fort, J., Rajderkar, D. A. 2020; 15 (7): 1110-1114

  Abstract

  Primary pulmonary artery sarcoma (PAS) is extremely rare in children. Nevertheless, distinguishing primary PAS from pulmonary embolism is critical to a child's survival. Primary PAS is commonly misdiagnosed as a pulmonary embolism due to similar presenting symptoms and radiographic findings. However, compared to adults, pulmonary embolism is rare in children, especially in patients who do not have predisposing factors or hypercoagulable state. We present a child with primary PAS which mimicked pulmonary embolism on presentation but eventually was resected and is doing well 5 years after resection. In the absence of predisposing factors or hypercoagulable state, solid tumors such as primary PAS should be considered when assessing a pediatric patient with presumed pulmonary embolism.

  View details for DOI 10.1016/j.radcr.2020.05.016

  View details for PubMedID 32477441

  View details for PubMedCentralID PMC7248585

• Eukaryotic initiation factor 4E binding protein family of proteins: sentinels at a translational control checkpoint in lung tumor defense. Cancer research Kim, Y. Y., Von Weymarn, L., Larsson, O., Fan, D., Underwood, J. M., Peterson, M. S., Hecht, S. S., Polunovsky, V. A., Bitterman, P. B. 2009; 69 (21): 8455-62

  Abstract

  The usurping of translational control by sustained activation of translation initiation factors is oncogenic. Here, we show that the primary negative regulators of these oncogenic initiation factors--the 4E-BP protein family--operate as guardians of a translational control checkpoint in lung tumor defense. When challenged with the tobacco carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), 4ebp1(-/-)/4ebp2(-/-) mice showed increased sensitivity to tumorigenesis compared with their wild-type counterparts. The 4E-BP-deficient state per se creates pro-oncogenic, genome-wide skewing of the molecular landscape, with translational activation of genes governing angiogenesis, growth, and proliferation, and translational activation of the precise cytochrome p450 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites. Our study provides in vivo proof for a translational control checkpoint in lung tumor defense.

  View details for DOI 10.1158/0008-5472.CAN-09-1923

  View details for PubMedID 19843855

  View details for PubMedCentralID PMC2805259