Zachary Hartman

Overview:

My research interests encompass studies of immunity and inflammation in the context of developing and established cancers. These research interests involve studies of inflammation in the genesis and maintenance of specific cancer types (principally breast and ovarian), as well as the impact of inflammation on tumor metastasis and the tumor microenvironment.  My group is also involved in strategies to modulate the immune response to tumors, which involves the use of novel immunotherapeutic strategies and development of vaccines to specific oncogenic targets.  The major focus of my lab is in uncovering strategies to modulate tumor-derived inflammation and tumor-specific immunity that will translate into clinically efficacious therapies in patients.

Positions:

Associate Professor in Surgery

Surgery, Surgical Sciences
School of Medicine

Associate Professor in Pathology

Pathology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Education:

Ph.D. 2006

Duke University

Post-Doctoral Fellow

Duke University

Post Doctoral Fellow, Md Anderson Cancer Center

University of Texas Medical School, Houston

Grants:

A Neoepitope Subunit Vaccine Targeting the Mutated Estrogen Receptor Ligand Binding Domain to Treat and Prevent Endocrine Resistant ER+ Breast Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
Department of Defense
Role
Principal Investigator
Start Date
End Date

Study of LAMP Vaccines in HER2+ Breast Cancer

Administered By
Surgery, Surgical Sciences
Awarded By
Immunomic Therapeutics, Inc.
Role
Principal Investigator
Start Date
End Date

Investigation of stimulating stress response mechanisms to enhance antibody dependent cellular phagocytosis

Administered By
Surgery, Surgical Sciences
Awarded By
Bantam Pharmaceutical, LLC
Role
Principal Investigator
Start Date
End Date

Investigating the adaptive immune response to dormant tumor cells

Administered By
Surgery, Surgical Sciences
Awarded By
American Cancer Society, Inc.
Role
Principal Investigator
Start Date
End Date

Investigation of LAMP anti-tumor vaccines

Administered By
Surgery, Surgical Sciences
Awarded By
Immunomic Therapeutics, Inc.
Role
Principal Investigator
Start Date
End Date

Publications:

How can we create precision immunotherapy as standard in breast cancer?

Authors
MLA Citation
Hartman, Zachary C. “How can we create precision immunotherapy as standard in breast cancer?Expert Rev Anticancer Ther, vol. 21, no. 11, Nov. 2021, pp. 1179–81. Pubmed, doi:10.1080/14737140.2021.1951241.
URI
https://scholars.duke.edu/individual/pub1488189
PMID
34213990
Source
pubmed
Published In
Expert Rev Anticancer Ther
Volume
21
Published Date
Start Page
1179
End Page
1181
DOI
10.1080/14737140.2021.1951241

HSP90-specific nIR probe identifies aggressive prostate cancers: translation from preclinical models to a human phase I study.

A noninvasive test to discriminate indolent prostate cancers from lethal ones would focus treatment where necessary while reducing over-treatment. We exploited the known activity of heat shock protein 90 (Hsp90) as a chaperone critical for the function of numerous oncogenic drivers, including the androgen receptor and its variants, to detect aggressive prostate cancer. We linked a near infrared fluorescing molecule to an HSP90 binding drug and demonstrated that this probe (designated HS196) was highly sensitive and specific for detecting implanted prostate cancer cell lines with greater uptake by more aggressive subtypes. In a phase I human study, systemically administered HS196 could be detected in malignant nodules within prostatectomy specimens. Single-cell RNA sequencing identified uptake of HS196 by malignant prostate epithelium from the peripheral zone (AMACR+ERG+EPCAM+ cells), including SYP+ neuroendocrine cells that are associated with therapeutic resistance and metastatic progression. A theranostic version of this molecule is under clinical testing.
Authors
Osada, T; Crosby, EJ; Kaneko, K; Snyder, JC; Ginzel, JD; Acharya, CR; Yang, X-Y; Polascik, TJ; Spasojevic, I; Nelson, RC; Hobeika, A; Hartman, ZC; Neckers, LM; Rogatko, A; Hughes, PF; Huang, J; Morse, MA; Haystead, T; Lyerly, HK
MLA Citation
Osada, Takuya, et al. “HSP90-specific nIR probe identifies aggressive prostate cancers: translation from preclinical models to a human phase I study.Mol Cancer Ther, Oct. 2021. Pubmed, doi:10.1158/1535-7163.MCT-21-0334.
URI
https://scholars.duke.edu/individual/pub1499234
PMID
34675120
Source
pubmed
Published In
Mol Cancer Ther
Published Date
DOI
10.1158/1535-7163.MCT-21-0334

HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.

HER2-positive breast cancers are among the most heterogeneous breast cancer subtypes. The early amplification of HER2 and its known oncogenic isoforms provide a plausible mechanism in which distinct programs of tumor heterogeneity could be traced to the initial oncogenic event. Here a Cancer rainbow mouse simultaneously expressing fluorescently barcoded wildtype (WTHER2), exon-16 null (d16HER2), and N-terminally truncated (p95HER2) HER2 isoforms is used to trace tumorigenesis from initiation to invasion. Tumorigenesis was visualized using whole-gland fluorescent lineage tracing and single-cell molecular pathology. We demonstrate that within weeks of expression, morphologic aberrations were already present and unique to each HER2 isoform. Although WTHER2 cells were abundant throughout the mammary ducts, detectable lesions were exceptionally rare. In contrast, d16HER2 and p95HER2 induced rapid tumor development. d16HER2 incited homogenous and proliferative luminal-like lesions which infrequently progressed to invasive phenotypes whereas p95HER2 lesions were heterogenous and invasive at the smallest detectable stage. Distinct cancer trajectories were observed for d16HER2 and p95HER2 tumors as evidenced by oncogene-dependent changes in epithelial specification and the tumor microenvironment. These data provide direct experimental evidence that intratumor heterogeneity programs begin very early and well in advance of screen or clinically detectable breast cancer. IMPLICATIONS: Although all HER2 breast cancers are treated equally, we show a mechanism by which clinically undetected HER2 isoforms program heterogenous cancer phenotypes through biased epithelial specification and adaptations within the tumor microenvironment.
Authors
Ginzel, JD; Acharya, CR; Lubkov, V; Mori, H; Boone, PG; Rochelle, LK; Roberts, WL; Everitt, JI; Hartman, ZC; Crosby, EJ; Barak, LS; Caron, MG; Chen, JQ; Hubbard, NE; Cardiff, RD; Borowsky, AD; Lyerly, HK; Snyder, JC
MLA Citation
Ginzel, Joshua D., et al. “HER2 Isoforms Uniquely Program Intratumor Heterogeneity and Predetermine Breast Cancer Trajectories During the Occult Tumorigenic Phase.Mol Cancer Res, vol. 19, no. 10, Oct. 2021, pp. 1699–711. Pubmed, doi:10.1158/1541-7786.MCR-21-0215.
URI
https://scholars.duke.edu/individual/pub1485787
PMID
34131071
Source
pubmed
Published In
Mol Cancer Res
Volume
19
Published Date
Start Page
1699
End Page
1711
DOI
10.1158/1541-7786.MCR-21-0215

Mechanisms of Therapeutic Antitumor Monoclonal Antibodies.

Monoclonal antibodies (mAb) are a major component of cancer therapy. In this review, we summarize the different therapeutic mAbs that have been successfully developed against various tumor-expressed antigens and examine our current understanding of their different mechanisms of antitumor action. These mechanisms of action (MOA) largely center on the stimulation of different innate immune effector processes, which appear to be principally responsible for the efficacy of most unconjugated mAb therapies against cancer. This is evident in studies of mAbs targeting antigens for hematologic cancers, with emerging data also demonstrating the critical nature of innate immune-mediated mechanisms in the efficacy of anti-HER2 mAbs against solid HER2<sup>+</sup> cancers. Although HER2-targeted mAbs were originally described as inhibitors of HER2-mediated signaling, multiple studies have since demonstrated these mAbs function largely through their engagement with Fc receptors to activate innate immune effector functions as well as complement activity. Next-generation mAbs are capitalizing on these MOAs through improvements to enhance Fc-activity, although regulation of these mechanisms may vary in different tumor microenvironments. In addition, novel antibody-drug conjugates have emerged as an important means to activate different MOAs. Although many unknowns remain, an improved understanding of these immunologic MOAs will be essential for the future of mAb therapy and cancer immunotherapy.
Authors
Tsao, L-C; Force, J; Hartman, ZC
MLA Citation
Tsao, Li-Chung, et al. “Mechanisms of Therapeutic Antitumor Monoclonal Antibodies.Cancer Research, vol. 81, no. 18, Sept. 2021, pp. 4641–51. Epmc, doi:10.1158/0008-5472.can-21-1109.
URI
https://scholars.duke.edu/individual/pub1485650
PMID
34145037
Source
epmc
Published In
Cancer Research
Volume
81
Published Date
Start Page
4641
End Page
4651
DOI
10.1158/0008-5472.can-21-1109

Progesterone promotes immunomodulation and tumor development in the murine mammary gland.

BACKGROUND: Clinical studies have linked usage of progestins (synthetic progesterone [P4]) to breast cancer risk. However, little is understood regarding the role of native P4, signaling through the progesterone receptor (PR), in breast tumor formation. Recently, we reported a link between PR and immune signaling pathways, showing that P4/PR can repress type I interferon signaling pathways. Given these findings, we sought to investigate whether P4/PR drive immunomodulation in the mammary gland and promote tumor formation. METHODS: To determine the effect of P4 on immune cell populations in the murine mammary gland, mice were treated with P4 or placebo pellets for 21 days. Immune cell populations in the mammary gland, spleen, and inguinal lymph nodes were subsequently analyzed by flow cytometry. To assess the effect of PR overexpression on mammary gland tumor development as well as immune cell populations in the mammary gland, a transgenic mouse model was used in which PR was overexpressed throughout the entire mouse. Immune cell populations were assessed in the mammary glands, spleens, and inguinal lymph nodes of 6-month-old transgenic and control mice by flow cytometry. Transgenic mice were also monitored for mammary gland tumor development over a 2-year time span. Following development of mammary gland tumors, immune cell populations in the tumors and spleens of transgenic and control mice were analyzed by flow cytometry. RESULTS: We found that mice treated with P4 exhibited changes in the mammary gland indicative of an inhibited immune response compared with placebo-treated mice. Furthermore, transgenic mice with PR overexpression demonstrated decreased numbers of immune cell populations in their mammary glands, lymph nodes, and spleens. On long-term monitoring, we determined that multiparous PR-overexpressing mice developed significantly more mammary gland tumors than control mice. Additionally, tumors from PR-overexpressing mice contained fewer infiltrating immune cells. Finally, RNA sequencing analysis of tumor samples revealed that immune-related gene signatures were lower in tumors from PR-overexpressing mice as compared with control mice. CONCLUSION: Together, these findings offer a novel mechanism of P4-driven mammary gland tumor development and provide rationale in investigating the usage of antiprogestin therapies to promote immune-mediated elimination of mammary gland tumors.
Authors
Werner, LR; Gibson, KA; Goodman, ML; Helm, DE; Walter, KR; Holloran, SM; Trinca, GM; Hastings, RC; Yang, HH; Hu, Y; Wei, J; Lei, G; Yang, X-Y; Madan, R; Molinolo, AA; Markiewicz, MA; Chalise, P; Axelrod, ML; Balko, JM; Hunter, KW; Hartman, ZC; Lange, CA; Hagan, CR
MLA Citation
Werner, Lauryn R., et al. “Progesterone promotes immunomodulation and tumor development in the murine mammary gland.J Immunother Cancer, vol. 9, no. 5, May 2021. Pubmed, doi:10.1136/jitc-2020-001710.
URI
https://scholars.duke.edu/individual/pub1482287
PMID
33958486
Source
pubmed
Published In
Journal for Immunotherapy of Cancer
Volume
9
Published Date
DOI
10.1136/jitc-2020-001710