Takuya Osada

Positions:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

M.D. 1986

University of Tokyo (Japan)

Ph.D. 1997

University of Tokyo (Japan)

Grants:

Dendritic Cell Mobilization and Active Immunotherapy

Awarded By
National Institutes of Health
Role
Investigator
Start Date
End Date

Redirecting Specificity of Viral Specific T Cells

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Research Scientist
Start Date
End Date

Visualizing tumor heterogeneity in an immune intact and autochthonous mouse model of breast cancer

Administered By
Surgery, Surgical Sciences
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Therapeutic targeting of breast cancer and host immune responses at inflection points in the disease trajectory

Awarded By
Department of Defense
Role
Co Investigator
Start Date
End Date

Publications:

Abstract 3731: A novel heat shock protein 90-targeted photosensitizer (HS-201) enables enhanced tumor-specific photodynamic therapy of inflammatory breast cancers

<jats:title>Abstract</jats:title> <jats:p>Background: Photodynamic therapy (PDT) is an effective local anti-cancer modality applied for the treatment of early stage disease and palliation of advanced disease, and could be used in managing inflammatory breast cancer (IBC). Although PDT can be focused by limiting the area of near infrared (nIR) light exposure, normal tissue injury due to the photosensitizer (PS) uptake by non-tumor tissues remains a barrier to broader applicability. We reported that selective delivery of a compound to malignant cells by exploiting their heat shock protein 90 (Hsp90) activity could be used for imaging breast cancers. This work was extended by the development of an Hsp90 targeted PS (HS201), in which a well characterized PS, verteporfin (VP), has been chemically tethered to a small molecule Hsp90 inhibitor and assessed the tumor-specificity and antitumor efficacy of HS201-based PDT (HS201-PDT).</jats:p> <jats:p>Methods &amp; Results: HS201 was taken up by human breast cancer cell lines, including IBC in vitro more readily than VP, resulting in increased tumor killing in vitro after exposure to a laser with a 690 nm wavelength. The in vivo selectively of HS201 uptake in tumor tissue was confirmed in both human breast cancer xenograft models and spontaneous tumors from HER2-transgenic mice. HS201 accumulation in the tumor was dramatically enhanced after the first laser exposure due to the feed forward increase in Hsp90 expression in the treated tumor cells, and thus a repeated laser exposure was conducted to enhance antitumor effects. This strategy enhanced antitumor effects, as MDA-MB-231 tumors implanted into SCID-beige mice responded to HS201-PDT but not to VP-PDT. Human xenograft breast cancer cell lines, including the IBC cell lines SUM149 and KPL-4, as well as non-IBC cell line BT474M1 and the patient-derived breast cancer xenograft HCI-013, were also tested in SCID-beige mice and demonstrated significantly suppressed tumor growth by HS201-PDT.</jats:p> <jats:p>Conclusions: HS201 showed selective uptake and longer retention by tumor cells, including IBC, especially when the tumors were exposed to local laser treatment. Due to the advantage of this feed-forward control of HS201 distribution, HS201-PDT demonstrated superior anti-tumor effects compared to VP-PDT against various human breast cancer xenografts in mice. These results suggest that HS201-PDT may be used in managing IBC, and may have an important role in anti-cancer therapy.</jats:p> <jats:p>Citation Format: Kensuke Kaneko, Takuya Osada, Philip F. Hughes, Timothy A. Haystead, Michael A. Morse, Herbert K. Lyerly. A novel heat shock protein 90-targeted photosensitizer (HS-201) enables enhanced tumor-specific photodynamic therapy of inflammatory breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3731.</jats:p>
Authors
Kaneko, K; Osada, T; Hughes, PF; Haystead, TA; Morse, MA; Lyerly, HK
MLA Citation
Kaneko, Kensuke, et al. “Abstract 3731: A novel heat shock protein 90-targeted photosensitizer (HS-201) enables enhanced tumor-specific photodynamic therapy of inflammatory breast cancers.” Cancer Research, vol. 79, no. 13_Supplement, American Association for Cancer Research (AACR), 2019, pp. 3731–3731. Crossref, doi:10.1158/1538-7445.am2019-3731.
URI
https://scholars.duke.edu/individual/pub1417346
Source
crossref
Published In
Cancer Research
Volume
79
Published Date
Start Page
3731
End Page
3731
DOI
10.1158/1538-7445.am2019-3731

Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients

<jats:title>Abstract</jats:title> <jats:p>Background: Immune-based therapy for metastatic breast cancer has had limited success. Strategies to augment adaptive immunity include vaccines targeting genomic amplifications like Human Epidermal Growth Factor Type 2 (HER2), an established driver of malignancy. Using a novel alphaviral vector, we constructed a vaccine encoding a portion of HER2 (VRP-HER2).</jats:p> <jats:p>Methods: In preclinical studies, mice were immunized before or after implantation of hHER2+ tumor cells and HER2-specific immune responses and anti-tumor function were assessed. We then translated this vaccine into a phase I clinical trial in which subjects with advanced HER2-overexpressing breast cancers received VRP-HER2 every 2 weeks for a total of three doses (cohort 1). In cohort 2, subjects received the same dose of VRP-HER2 along with a standard HER2 targeted therapy.</jats:p> <jats:p>Results: VRP-HER2 induced HER2-specific T cell and antibody responses while controlling tumor growth in murine models. Vaccination with VRP-HER2 was well tolerated in both patient cohorts. PFS was modest, while median OS was 50.2 months in cohort 1 and 32.7 months in cohort 2. In cohort 2, there is one partial response and two patients with continued stable disease. Vaccine induced anti-HER2 antibodies and T cells were identified. Increased perforin expression by memory CD8 T cells post vaccination significantly correlated with improved PFS.</jats:p> <jats:p>Conclusions: VRP-HER2 led to an increase in perforin expressing HER2-specific memory CD8 T cells in preclinical and clinical studies, and had profound antitumor effects in murine models. The generation of HER2-specific memory CD8 T cells was significantly correlated with increased PFS in patients. Subsequent studies will seek to enhance T cell activity by combination with anti-PD-1/PD-L1 antibodies.</jats:p> <jats:p>Citation Format: Crosby EJ, Gwin WR, Chang S, Maecker HT, Lubkov V, Snyder JC, Broadwater G, Hyslop T, Osada T, Hobeika AC, Hartman ZC, Morse MA, Lyerly HK. CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-09-16.</jats:p>
Authors
Crosby, EJ; Gwin, WR; Chang, S; Maecker, HT; Lubkov, V; Snyder, JC; Broadwater, G; Hyslop, T; Osada, T; Hobeika, AC; Hartman, ZC; Morse, MA; Lyerly, HK
MLA Citation
Crosby, E. J., et al. “Abstract P2-09-16: CD8 T cells induced by novel alphaviral vector predict improved progression free survival in advanced HER2+ breast cancer patients.” Cancer Research, vol. 79, no. 4_Supplement, American Association for Cancer Research (AACR), 2019. Crossref, doi:10.1158/1538-7445.sabcs18-p2-09-16.
URI
https://scholars.duke.edu/individual/pub1404161
Source
crossref
Published In
Cancer Research
Volume
79
Published Date
DOI
10.1158/1538-7445.sabcs18-p2-09-16

Abstract 1859: Hsp90 targeted near infrared molecular imaging to detect mammografically occult invasive lobular breast cancer

<jats:title>Abstract</jats:title> <jats:p>Background: Early diagnosis of Invasive lobular carcinomas (ILCs) is clinically challenging due to its histopathologic features making it difficult to detect using mammography. Because of the diffuse infiltration of ILC cells into the surrounding stroma, ILC is also associated with a higher incidence of positive resection margins after breast-conserving surgery. Therefore, there is a significant unmet need for improved imaging for early detection, clinical staging, and possibly intraoperative imaging to assess surgical margins. We propose to detect mammografically occult ILC by the in vivo detecting of malignant signaling pathways activated in ILC. Heat shock protein 90 (Hsp90) comprises 1-3% of the total cellular protein in most cells and acts as a molecular chaperone for more than 200 reported client proteins. Recently, we developed a series of tethered Hsp90 inhibitors that specifically target a tumor specific form of Hsp90 associated with poor outcomes. Using near infrared (nIR) probe-tethered Hsp90 inhibitors, we demonstrated that Hsp90 is actively re-internalized and can be used to image murine and human breast cancer in vitro and in vivo.</jats:p> <jats:p>Methods and Results: We tested the imaging efficacy of the nIR-tethered Hsp90 inhibitor, HS196, in ILC models in vitro and in vivo. An inactive structural analog HS199 was used as a control to monitor for non-specific (non-Hsp90 dependent) uptake. Two ILC cell lines, MDA-MB-134 VI and SUM44-PE, and one patient-derived ILC xenograft, HCI-013 EI, were tested. nIR signals of HS196 in vitro and in vivo were detected by Odyssey (LI-COR) and Pearl Trilogy (LI-COR)/SPY ELITE imager (Novadaq), respectively. High uptake of HS196 was observed in vitro by both cell lines (&amp;gt; 1 µM), while the control HS199 resulted in weaker nIR signals in these cells. In vivo imaging efficacy of HS196 was tested using HCI-013 EI xenograft in SCID-beige mice. After injection of 10 nmol compounds via tail vein, quick and stronger accumulation and longer retention of the HS196 in the ILC xenograft was observed, while HS199 showed significantly weaker accumulation and faster clearance (by 24 h after injection). Significant uptake of HS196 by HCI-013 EI tumors was confirmed by ex vivo imaging of tumors 24 h after compound injection. Histological and flow cytometry analysis of HCI-013 EI tumors showed strong nIR signals in tumor cells.</jats:p> <jats:p>Conclusions: The non-radioactive, nIR imaging strategy, using a novel nIR-Hsp90 inhibitor compound, HS196, was effective in the non-invasive imaging of ILC tumors. This finding suggests that new molecular imaging techniques, not dependent on micro calcifications or architectural distortion, may be a novel strategy to met the need of ILC patients to detect, clinically stage and assess margins during surgical resection. Ongoing pre-clinical models will be employed and first in human testing of this approach in planned.</jats:p> <jats:p>Citation Format: Takuya Osada, Kensuke Kaneko, Zachary Hartman, Amy Hobeika, Philip Hughes, Timothy Haystead, Michael Morse, H. Kim Lyerly. Hsp90 targeted near infrared molecular imaging to detect mammografically occult invasive lobular breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1859. doi:10.1158/1538-7445.AM2017-1859</jats:p>
Authors
Osada, T; Kaneko, K; Hartman, Z; Hobeika, A; Hughes, P; Haystead, T; Morse, M; Lyerly, HK
MLA Citation
Osada, Takuya, et al. “Abstract 1859: Hsp90 targeted near infrared molecular imaging to detect mammografically occult invasive lobular breast cancer.” Cancer Research, vol. 77, no. 13_Supplement, American Association for Cancer Research (AACR), 2017, pp. 1859–1859. Crossref, doi:10.1158/1538-7445.am2017-1859.
URI
https://scholars.duke.edu/individual/pub1347270
Source
crossref
Published In
Cancer Research
Volume
77
Published Date
Start Page
1859
End Page
1859
DOI
10.1158/1538-7445.am2017-1859

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

Human epidermal growth factor receptor HER3 has been implicated in promoting the aggressiveness and metastatic potential of breast cancer. Upregulation of HER3 has been found to be a major mechanism underlying drug resistance to EGFR and HER2 tyrosine kinase inhibitors and to endocrine therapy in the treatment of breast cancer. Thus, agents that reduce HER3 expression at the plasma membrane may synergize with current therapies and offer a novel therapeutic strategy to improve treatment.
Authors
Ren, XR; Wang, J; Osada, T; Mook, RA; Morse, MA; Barak, LS; Lyerly, HK; Chen, W
MLA Citation
Ren, X. R., et al. “Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.Breast Cancer Res, vol. 17, no. 1, Dec. 2015, p. 528. Pubmed, doi:10.1186/s13058-015-0528-9.
URI
https://scholars.duke.edu/individual/pub1060504
PMID
25778364
Source
pubmed
Published In
Breast Cancer Res
Volume
17
Published Date
Start Page
528
DOI
10.1186/s13058-015-0528-9

Abstract C86: Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.

<jats:title>Abstract</jats:title> <jats:p>Hsp90 inhibitors have demonstrated unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained but could be influenced by ectopically expressed Hsp90 in tumors. We have synthesized novel Hsp90 inhibitors that can carry optical or radioiodinated probes via a PEG tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein is occurring at the plasma membrane. In mice, we show exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors targeting ectopic Hsp90 can be used to detect breast cancer malignancies through non-invasive imaging.</jats:p> <jats:p>Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C86.</jats:p> <jats:p>Citation Format: Jared J. Barrott, Aaron P. Smith, Takuya Osada, Nimmi Ramanujam, Michael R. Zalutsky, Kim Lyerly, Timothy A. J. Haystead. Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C86.</jats:p>
MLA Citation
Barrott, Jared J., et al. “Abstract C86: Tethered Hsp90 inhibitors carrying optical or radioiodinated probes reveal selective internalization of ectopic Hsp90 in malignant breast tumor cells.Molecular Cancer Therapeutics, vol. 12, no. 11_Supplement, American Association for Cancer Research (AACR), 2013, pp. C86–C86. Crossref, doi:10.1158/1535-7163.targ-13-c86.
URI
https://scholars.duke.edu/individual/pub1090811
Source
crossref
Published In
Molecular Cancer Therapeutics
Volume
12
Published Date
Start Page
C86
End Page
C86
DOI
10.1158/1535-7163.targ-13-c86