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1. Phase 1 dose escalation study of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine in patients with myeloid malignancies.

Author

DiNardo, Courtney D., Olin, Rebecca, Wang, Eunice S., Skikne, Barry, Rosenthal, Joseph, Kumar, Prasanna, Sumi, Hiroyuki, Hizukuri, Yoshiyuki, Hong, Ying, Patel, Parul, Seki, Takahiko, Duan, Tao, Lesegretain, Arnaud, and Andreeff, Michael

Subjects
MYELODYSPLASTIC syndromes, ACUTE myeloid leukemia, HEMATOLOGIC malignancies, MOUSE leukemia, POLYMERASE chain reaction
Abstract

Background: Mouse double minute‐2 homolog (MDM2) plays a key role in downregulating p53 activity in hematologic malignancies, and its overexpression is associated with poor outcomes. Methods: This phase 1 study assessed the safety and efficacy of different dosing regimens of the MDM2 inhibitor milademetan as monotherapy and in combination with azacitidine (AZA) in patients with relapsed or refractory acute myeloid leukemia or high‐risk myelodysplastic syndromes. Results: Seventy‐four patients (monotherapy, n = 57; milademetan‐AZA combination, n = 17) were treated. The maximum tolerated dose of milademetan was 160 mg once daily given for the first 14–21 days of 28‐day cycles as monotherapy and on Days 5–14 in combination with AZA. Dose‐limiting toxicities were gastrointestinal, fatigue, or renal/electrolyte abnormalities. Treatment‐emergent adverse events related to milademetan occurred in 82.5% and 64.7% of participants in the monotherapy and AZA combination arms, respectively. Two participants (4.2%) in the monotherapy arm achieved complete remission (CR), and 1 (2.1%) achieved CR with incomplete blood count recovery (CRi). Two participants (13.3%) achieved CRi in the combination arm. New TP53 mutations, detected only during milademetan monotherapy, were found pre‐existing below standard detection frequency by droplet digital polymerase chain reaction. Interpretation: Milademetan was relatively well tolerated in this population; however, despite signals of activity, clinical efficacy was minimal. [ABSTRACT FROM AUTHOR]

Published
2024
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2. Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias

Author

Nishida, Yuki, primary, Ishizawa, Jo, additional, Ayoub, Edward, additional, Montoya, Rafael Heinz, additional, Ostermann, Lauren B., additional, Muftuoglu, Muharrem, additional, Ruvolo, Vivian R, additional, Patsilevas, Tallie, additional, Scruggs, Darah A., additional, Khazaei, Shayaun, additional, Mak, Po Yee, additional, Tao, Wenjing, additional, Carter, Bing Z., additional, Boettcher, Steffen, additional, Ebert, Benjamin L., additional, Daver, Naval G., additional, Konopleva, Marina, additional, Seki, Takahiko, additional, Kojima, Kensuke, additional, and Andreeff, Michael, additional

Published
2023
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3. Selective inhibition of mutant IDH1 by DS-1001b ameliorates aberrant histone modifications and impairs tumor activity in chondrosarcoma

Author

Nakagawa, Makoto, Nakatani, Fumihiko, Matsunaga, Hironori, Seki, Takahiko, Endo, Makoto, Ogawara, Yoko, Machida, Yukino, Katsumoto, Takuo, Yamagata, Kazutsune, Hattori, Ayuna, Fujita, Shuhei, Aikawa, Yukiko, Ishikawa, Takamasa, Soga, Tomoyoshi, Kawai, Akira, Chuman, Hirokazu, Yokoyama, Nobuhiko, Fukushima, Suguru, Yahiro, Kenichiro, Kimura, Atsushi, Shimada, Eijiro, Hirose, Takeshi, Fujiwara, Toshifumi, Setsu, Nokitaka, Matsumoto, Yoshihiro, Iwamoto, Yukihide, Nakashima, Yasuharu, and Kitabayashi, Issay

Published
2019
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4. Enhanced TP53 reactivation disrupts MYC transcriptional program and overcomes venetoclax resistance in acute myeloid leukemias

Author

Nishida, Yuki; https://orcid.org/0000-0001-5827-7406, Ishizawa, Jo; https://orcid.org/0000-0001-8566-7370, Ayoub, Edward; https://orcid.org/0000-0003-1321-0114, Montoya, Rafael Heinz; https://orcid.org/0000-0003-2335-5894, Ostermann, Lauren B; https://orcid.org/0000-0002-3330-2174, Muftuoglu, Muharrem; https://orcid.org/0000-0001-8100-8554, Ruvolo, Vivian R; https://orcid.org/0000-0003-4363-7258, Patsilevas, Tallie, Scruggs, Darah A, Khazaei, Shayaun; https://orcid.org/0009-0004-2677-8176, Mak, Po Yee, Tao, Wenjing, Carter, Bing Z; https://orcid.org/0000-0003-0076-0889, Boettcher, Steffen; https://orcid.org/0000-0001-9937-0957, Ebert, Benjamin L; https://orcid.org/0000-0003-0197-5451, Daver, Naval G; https://orcid.org/0000-0001-7103-373X, Konopleva, Marina, Seki, Takahiko, Kojima, Kensuke; https://orcid.org/0000-0003-4138-0604, Andreeff, Michael; https://orcid.org/0000-0002-1144-1958, Nishida, Yuki; https://orcid.org/0000-0001-5827-7406, Ishizawa, Jo; https://orcid.org/0000-0001-8566-7370, Ayoub, Edward; https://orcid.org/0000-0003-1321-0114, Montoya, Rafael Heinz; https://orcid.org/0000-0003-2335-5894, Ostermann, Lauren B; https://orcid.org/0000-0002-3330-2174, Muftuoglu, Muharrem; https://orcid.org/0000-0001-8100-8554, Ruvolo, Vivian R; https://orcid.org/0000-0003-4363-7258, Patsilevas, Tallie, Scruggs, Darah A, Khazaei, Shayaun; https://orcid.org/0009-0004-2677-8176, Mak, Po Yee, Tao, Wenjing, Carter, Bing Z; https://orcid.org/0000-0003-0076-0889, Boettcher, Steffen; https://orcid.org/0000-0001-9937-0957, Ebert, Benjamin L; https://orcid.org/0000-0003-0197-5451, Daver, Naval G; https://orcid.org/0000-0001-7103-373X, Konopleva, Marina, Seki, Takahiko, Kojima, Kensuke; https://orcid.org/0000-0003-4138-0604, and Andreeff, Michael; https://orcid.org/0000-0002-1144-1958

Abstract

The tumor suppressor TP53 is frequently inactivated in a mutation-independent manner in cancers and is reactivated by inhibiting its negative regulators. We here cotarget MDM2 and the nuclear exporter XPO1 to maximize transcriptional activity of p53. MDM2/XPO1 inhibition accumulated nuclear p53 and elicited a 25- to 60-fold increase of its transcriptional targets. TP53 regulates MYC, and MDM2/XPO1 inhibition disrupted the c-MYC-regulated transcriptome, resulting in the synergistic induction of apoptosis in acute myeloid leukemia (AML). Unexpectedly, venetoclax-resistant AMLs express high levels of c-MYC and are vulnerable to MDM2/XPO1 inhibition in vivo. However, AML cells persisting after MDM2/XPO1 inhibition exhibit a quiescence- and stress response-associated phenotype. Venetoclax overcomes that resistance, as shown by single-cell mass cytometry. The triple inhibition of MDM2, XPO1, and BCL2 was highly effective against venetoclax-resistant AML in vivo. Our results propose a novel, highly translatable therapeutic approach leveraging p53 reactivation to overcome nongenetic, stress-adapted venetoclax resistance.

Published
2023

5. Discovery of a Novel ATP-Competitive MEK Inhibitor DS03090629 that Overcomes Resistance Conferred by BRAF Overexpression in BRAF-Mutated Melanoma

Author

Takano, Kohei, primary, Munehira, Yoichi, additional, Hatanaka, Mana, additional, Murakami, Ryo, additional, Shibata, Yoshihiro, additional, Shida, Takeshi, additional, Takeuchi, Kosuke, additional, Takechi, Sho, additional, Tabata, Toshiki, additional, Shimada, Takashi, additional, Kishikawa, Shuhei, additional, Matsui, Yumi, additional, Ubukata, Osamu, additional, Seki, Takahiko, additional, and Kaneta, Yasuyuki, additional

Published
2023
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7. Enhanced p53 Activation By Dual Inhibition of MDM2 and XPO1 Disrupts MYC Transcriptional Program and Restores Sensitivity to BCL-2 Inhibition in Ven/HMA Resistant AML

Author

Nishida, Yuki, primary, Ishizawa, Jo, additional, Ayoub, Edward, additional, Patsilevas, Tallie, additional, Ostermann, Lauren, additional, Montoya, Rafael Heinz, additional, Muftuoglu, Muharrem, additional, Ruvolo, Vivian, additional, Mak, Po Yee, additional, Tao, Wenjing, additional, Carter, Bing Z, additional, Kojima, Kensuke, additional, Daver, Naval, additional, Lesegretain, Arnaud, additional, Seki, Takahiko, additional, Shacham, Sharon, additional, Konopleva, Marina, additional, and Andreeff, Michael, additional

Published
2021
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8. A Potent Blood–Brain Barrier-Permeable Mutant IDH1 Inhibitor Suppresses the Growth of Glioblastoma with IDH1 Mutation in a Patient-Derived Orthotopic Xenograft Model

Author

Machida, Yukino, primary, Nakagawa, Makoto, additional, Matsunaga, Hironori, additional, Yamaguchi, Masayuki, additional, Ogawara, Yoko, additional, Shima, Yutaka, additional, Yamagata, Kazutsune, additional, Katsumoto, Takuo, additional, Hattori, Ayuna, additional, Itoh, Masato, additional, Seki, Takahiko, additional, Nishiya, Yumi, additional, Nakamura, Koichi, additional, Suzuki, Kanae, additional, Imaoka, Tomoki, additional, Baba, Daichi, additional, Suzuki, Makoto, additional, Sampetrean, Oltea, additional, Saya, Hideyuki, additional, Ichimura, Koichi, additional, and Kitabayashi, Issay, additional

Published
2020
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9. A high fill factor and progressive scan PtSi Schottky-barrier IR-CCD image sensor using new wiring technology

Author

Tohyama, Shigeru, Masubuchi, Kouichi, Konuma, Kazuo, Azuma, Hiromi, Tanabe, Akihito, Utsumi, Hiroaki, Teranishi, Nobukazu, Takano, Eiji, Yamagata, Shigeki, Hijikawa, Minoru, Sahara, Hirokazu, Muramatsu, Toshio, Seki, Takahiko, Ono, Takeshi, and Goto, Hideki

Subjects
Image processing -- Equipment and supplies, Sensors -- Research, Business, Electronics, Electronics and electrical industries
Abstract

New wiring technology, known as CLOSE Wiring, is used to make high fill factor and a progressive scan PtSi Schottky-barrier IR-CCD image sensor. A 64.4% fill factor is obtained, in a 30 by 30 micro m pixel, a 3.9 by 3.9 mm image area and a 5.5 by 5.5 mm chip size, using this image sensor. A charge of 9.8 multiplied by 10 to 5th power can be managed by a 3.3 micro m wide vertical CCD. With a 50 mm f/1.3 lens and operating at 120 frames/sec the noise equivalent temperature difference is 0.099 K.

Published
1995

12. Predictive Gene Signatures Determine Tumor Sensitivity to MDM2 Inhibition

Author

Ishizawa, Jo, primary, Nakamaru, Kenji, additional, Seki, Takahiko, additional, Tazaki, Koichi, additional, Kojima, Kensuke, additional, Chachad, Dhruv, additional, Zhao, Ran, additional, Heese, Lauren, additional, Ma, Wencai, additional, Ma, Man Chun John, additional, DiNardo, Courtney, additional, Pierce, Sherry, additional, Patel, Keyur P., additional, Tse, Archie, additional, Davis, R. Eric, additional, Rao, Arvind, additional, and Andreeff, Michael, additional

Published
2018
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13. Discovery of Predictive Gene Signatures for Tumor Sensitivity to MDM2 Inhibition in Development of a Novel MDM2 Inhibitor DS-3032b

Author

Ishizawa, Jo, primary, Nakamaru, Kenji, additional, Seki, Takahiko, additional, Tazaki, Koichi, additional, Kojima, Kensuke, additional, Chachad, Dhruv, additional, DiNardo, Courtney D, additional, Pierce, Sherry, additional, Patel, Keyur P., additional, Tse, Archie, additional, Davis, R Eric, additional, Rao, Arvind, additional, and Andreeff, Michael, additional

Published
2016
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17. Abstract 3101: The mutant IDH1 inhibitor prevents growth of glioblastoma with IDH1 mutation in patient-derived xenograft (PDX) model

Author

Yukino Machida, Yoko Ogawara, Hironori Matsunaga, Kazushi Araki, Seki Takahiko, Koichi Ichimura, and Issay Kitabayashi

Subjects
Cancer Research, IDH1, business.industry, Mutant, medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Oncology, 030220 oncology & carcinogenesis, IDH1 Mutation, Cancer research, Medicine, In patient, business, 030217 neurology & neurosurgery, Glioblastoma
Abstract

Mutations in isocitrate dehydrogenase (IDH) 1 and 2 are frequently observed in acute myeloid leukemia (AML), glioma, and many other cancers. While wild-type IDHs convert isocitrate to α-ketoglutarate (α-KG), mutant IDHs convert α-KG to oncometabolite 2-hydroxyglutarate (2-HG), which dysregulates a set of α-KG-dependent dioxygenases, such as TETs, histone demethylases, EGLNs, and other enzymes. Because the role of mutant IDH is not necessary for normal cells, inhibitors directed against mutant IDH are expected to have minimum side effects as those of anti-cancer agents. We established a mouse AML model harboring IDH mutations by co-transducing four mutant genes that frequently occur simultaneously in human AML patients. Conditional deletion of the IDH mutant blocked 2HG production and maintenance of leukemia stem cells, resulting in survival of the AML mice. These results indicate that the IDH mutations are critical for the development and maintenance of AML stem cells. Based on these findings, we developed potent and specific inhibitors of mutant IDH1 and tested their effects on the mutant IDH1-dependent AML mouse model, created by introducing four mutant genes including mutant IDH1. The 2HG level was promptly and dramatically decreased in AML cells soon after treatment with the mutant IDH1 inhibitors, and the number of leukemia cells was reduced after a 4-week treatment. To test the effect of the mutant IDH1 inhibitor on glioblastoma, we have established a patient-derived xenograft (PDX) model of glioblastoma carrying IDH1 mutation, and tested the effect of the mutant IDH1 inhibitor on this model. The inhibitor reduced 2HG levels in tumors as well as in plasma. The inhibitor prevented the growth of the tumors with IDH1 mutation. On the other hand, the inhibitor did not affect the growth of the glioblastoma with wild type IDH1. Gene expression analysis identified a set of genes, of which expressions is changed by the IDH1 inhibitor. The most strongly upregulated gene is Glial fibrillary acidic protein (GFAP), which is a differentiation marker for astrocytes. Up-regulation of GFAP is confirmed by immune-staining and quantitative RT-PCR analyses. These results suggest that IDH inhibitor induces differentiation of the glioblastoma with IDH1 mutation. We have found that the glioblastoma is transplantable in mouse brain. We are now looking at effects of the inhibitor on this model. Taken together, the results indicate that IDH1 mutant inhibitors are effective for the treatment for AML as well as glioblastoma with IDH1 mutations. Citation Format: Yukino Machida, Yoko Ogawara, Koichi Ichimura, Hironori Matsunaga, Seki Takahiko, Kazushi Araki, Issay Kitabayashi. The mutant IDH1 inhibitor prevents growth of glioblastoma with IDH1 mutation in patient-derived xenograft (PDX) model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3101.

Published
2016

22. Bloom Helicase and DNA Topoisomerase IIIα Are Involved in the Dissolution of Sister Chromatids

Author

Seki, Masayuki, primary, Nakagawa, Takayuki, additional, Seki, Takahiko, additional, Kato, Genta, additional, Tada, Shusuke, additional, Takahashi, Yuriko, additional, Yoshimura, Akari, additional, Kobayashi, Takayuki, additional, Aoki, Ayako, additional, Otsuki, Makoto, additional, Habermann, Felix A., additional, Tanabe, Hideyuki, additional, Ishii, Yutaka, additional, and Enomoto, Takemi, additional

Published
2006
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25. Activation of p53 Enhances Antileukemia Activity of Bcr-Abl Tyrosine Kinase Inhibitors in a Murine Model of CML

Author

Carter, Bing Z, Mak, Po Yee, Mu, Hong, Mak, Duncan, Dettman, Ej, Cardone, Michael, Wang, Xiangmeng, Schober, Wendy, Tao, Wenjing, Seki, Takahiko, and Andreeff, Michael

Abstract

Although CML patients under Bcr-Abl tyrosine kinase inhibitor (TKI) therapy have experienced high response rates and long-time survival, 50% or more patients relapse upon therapy cessation, largely because TKIs do not eliminate CML stem cells. We previously reported that inhibition of antiapoptotic Bcl-2 proteins synergized with TKIs to eradicate CML stem/progenitor cells. The tumor suppressor p53 induces apoptosis in part by modulating Bcl-2 family proteins. Although rarely mutated in CML, p53 activity is antagonized by Bcr-Abl tyrosine kinase-regulated MDM2. We hypothesize that activation of p53 by MDM2 inhibition will synergize with TKIs to eliminate CML cells. Using an inducible transgenic Scl-tTa- BCR-ABLmouse model, we first determined the expression of p53 and its target genes in bone marrow (BM) cells of Tet-on (control) and Tet-off (CML) mice. We found markedly increased RNA levels of p53 and its targets Bax, Noxa, and MDM2 in CML as compared to control mice. Using CyTOF mass cytometry and cytofkid automatic subset detection/clustering based on the expression of cell surface markers, we then determined p53 and its target proteins in bulk and Lin-Sca-1+cKit+(LSK) populations at single cell levels and found overexpression of p53 and its targets such as Noxa in CML BM cells (CD45+) compared to controls. The differential expression was most pronounced in the LSK populations. For both control and CML mice, LSK cells expressed significantly higher p53 protein than their respective bulk cell population. We next evaluated the sensitivity of these cells to BH3 peptide priming. CML BM cells and more so LSK populations were more sensitive to BH3 peptides, especially to Noxa peptide than cells from control mice (P=0.044 in CD45+and P=0.0005 in LSK populations) suggesting that CML cells are more primed to apoptosis stimuli. Finally, we tested the antileukemia activity of combined MDM2 and Bcr-Abl inhibition in mice engrafted with BM cells from Scl-tTa- BCR-ABL/GFP mice. Combined inhibition of Bcr-Abl tyrosine kinase (imatinib) and MDM2 (DS-5272) strongly reduced BM leukemic populations and LSK cells, increased Noxa, decreased leukemia burden, and significantly prolonged survival (P=0.0021 vs. control). Median survival days for control, imatinib, DS-5272, and the combination groups were 85, 110, 155, and 248; respectively.

Published
2017
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26. Combined inhibition of MDM2 and BCR-ABL1 tyrosine kinase targets chronic myeloid leukemia stem/progenitor cells in a murine model.

Author

Carter BZ, Mak PY, Mu H, Wang X, Tao W, Mak DH, Dettman EJ, Cardone M, Zernovak O, Seki T, and Andreeff M

Subjects
Animals, Cell Proliferation, Disease Models, Animal, Drug Resistance, Neoplasm, Fusion Proteins, bcr-abl genetics, Mice, Neoplastic Stem Cells, Proto-Oncogene Proteins c-mdm2 genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive drug therapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Protein Kinase Inhibitors pharmacology
Abstract

Although highly effective, BCR-ABL1 tyrosine kinase inhibitors do not target chronic myeloid leukemia (CML) stem cells. Most patients relapse upon tyrosine kinase inhibitor therapy cessation. We reported previously that combined BCR-ABL1 and BCL-2 inhibition synergistically targets CML stem/progenitor cells. p53 induces apoptosis mainly by modulating BCL-2 family proteins. Although infrequently mutated in CML, p53 is antagonized by MDM2, which is regulated by BCR-ABL1 signaling. We hypothesized that MDM2 inhibition could sensitize CML cells to tyrosine kinase inhibitors. Using an inducible transgenic Scl-tTa- BCR-ABL1 murine CML model, we found, by RT-PCR and CyTOF proteomics increased p53 signaling in CML bone marrow (BM) cells compared with controls in CD45 + and linage-SCA-1 + C-KIT + populations. CML BM cells were more sensitive to exogenous BH3 peptides than controls. Combined inhibition of BCR-ABL1 with imatinib and MDM2 with DS-5272 increased NOXA level, markedly reduced leukemic linage-SCA-1 + C-KIT + cells and hematopoiesis, decreased leukemia burden, significantly prolonged the survival of mice engrafted with BM cells from Scl-tTa- BCR-ABL1 mice, and significantly decreased CML stem cell frequency in secondary transplantations. Our results suggest that CML stem/progenitor cells have increased p53 signaling and a propensity for apoptosis. Combined MDM2 and BCR-ABL1 inhibition targets CML stem/progenitor cells and has the potential to improve cure rates for CML., (Copyright© 2020 Ferrata Storti Foundation.)

Published
2020
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