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Pathology & Immunology

Houston, Texas

Pathology and Immunology
Pathology & Immunology
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David Spencer, Ph.D.

David Spencer photo

Professor, Departments of Pathology & Immunology and Urology, and the Program in Cell and Molecular Biology

Ph.D., Massachusetts Institute of Technology
Postdoctoral, Stanford University

E-mail: dspencer@bcm.edu

Research Interests: Prostate cancer progression and immunotherapy; gene therapy

Our lab focuses on understanding and treating prostate cancer, specifically using novel animal models and immunological approaches. This mission statement can sum up our approach to science:

A lucid understanding of the labyrinthine complexities of intracellular signaling networks is an important prerequisite for manipulating signaling and, thus, gene expression. Paradoxically, the ability to regulate the activity of a protein within a signaling cascade provides a powerful aid towards elucidating the contextual role of that protein. In other words, inducible proteins can be quite useful. While gene ablation and transgenic mice expressing constitutively active or dominant negative molecules have provided insight into the physiological roles of many genes, interpretations of the phenotypes of genetically altered mice are often limited by several factors: (i) signaling molecules or pathways may compensate for the hypo- or hyperactivity of others, (ii) signaling molecules have activities that are often redundant, and (iii) the inappropriate expression of many genes can be cytotoxic or cytostatic. In order to avoid these potentially confounding effects, the development of conditionally active proteins that can be spatially and/or temporarily regulated is needed.

With these factors in mind, our research has revolved around the further development and application of a novel tool for conditionally activating a wide spectrum of cellular processes in vivo, and to specifically apply this technology towards regulating signaling pathways that control cell viability and proliferation. Using membrane-permeable, synthetic molecules known as chemical inducers of dimerization (CIDs), we have found that we can conditionally regulate both cell surface receptors and intracellular signaling molecules, leading to apoptosis, proliferation, or other outcomes. These reagents will have broad biomedical applications.

More specifically, this work has led to the development of:

1. A novel dendritic cell (DC) vaccine platform, by which we can exquisitely manipulate the activation state of DCs in vivo. Regulation of a composite molecule with signaling elements from CD40 and TLRs has led to a potent vaccine against cancer. This vaccine is currently being tested in clinical trials for patients with metastatic castration-resistant prostate cancer.

Schematic representation of CID-mediated activation of inducible FGFR1 (iFGFR1) expressed in JOCK1 mouse prostates. The background is a heatmap image of the changes in gene expression observed during iFGFR1-mediated prostate cancer progression. These figures are bordered by a glandular structure from JOCK1 adenocarcinoma lesions, stained with Masson’s trichrome for collagen (blue). The gland itself is surrounded by neoplastic epithelial cells (red).

2. Inducible caspases (called iCaspases) and the demonstration of their utility in reducing or even elim inating prostate tumors in vivo. This work, coupled with efforts to increase the immunogenicity and TH1 environment of prostate tumors has led to a novel, effective preclinical prostate cancer vaccine. A clinical trial to study the utility of iCaspases as a “suicide gene” for adoptively transferred T cells is currently underway.

3. Inducible fibroblast growth factor receptors (iFGFRs) that have helped us understand the development and progression of prostate cancer. Targeting of these molecules to the prostates of transgenic mice has led to the first inducible and reversible model for prostate cancer and a better understanding of the role of epithelial-mesenchymal transitions (EMT) in cancer progression. Development and characterization of additional prostate cancer models based on manipulation of other key signaling molecules, such as beta-catenin and Sox9, are underway.

4. Inducible Akt (iAkt) that can conditionally protect cells from cytotoxic stimuli while minimizing the risk of transformation and tumor promotion. These molecules should lead to a number of new models for neoplasia, graft tolerance, ischemia/reperfusion resistance and more.

5. Several new prostate reporter lines, called EZC-Prostate that allow us to track metastasis and measure changes in prostate size in living animals.

6. An overall philosophy of treating disease using non-mutagenic approaches using endogenous signaling pathways.


Selected Publications:

  • Spencer, D.M., Wandless, T.J., Schreiber, S.L., Crabtree, G.R. Controlling signal transduction with synthetic ligands. Science 262:1019-1024, 1993.
  • Xiaoming Xie, Xiuqin Zhao, Yuanfang Liu, Jianfeng Zhang, Robert J Matusik, Kevin M Slawin, David M Spencer. (01) Adenovirus-mediated tissue-targeted expression of a caspase-9-based artificial death switch for the treatment of prostate cancer. Cancer Research, 61,6795-6804.
  • Benyi Li, Smruti A. Desai, Rebecca A. MacCorkle-Chosnek, Liangfen Fan, David M. Spencer (02) A Novel Conditional Akt “Survival Switch” Reversibly Protects Cells From Apoptosis. Gene Therapy, 9, 233-244.
  • Kevin W. Freeman, Bryan E. Welm, Rama D. Gangula, Jeffrey M. Rosen, Michael Ittmann, Norman M. Greenberg, David M. Spencer (2003) Inducible prostate intraepithelial neoplasia with reversible hyperplasia in conditional FGFR1-expressing mice. Cancer Res. 63, 8256-8263.
  • Brent A. Hanks, Jianghong Jiang, Rana A. Singh, Weitao Song, Michael A. Barry, Kevin M. Slawin, and David M. Spencer (2005) Reengineered CD40 Receptor Enables Potent Pharmacological in vivo Activation of Dendritic Cell Cancer Vaccines, Nature Medicine 11 (2), 130-137.
  • Ekaterina Yu. Nikitina, Smruti A. Desai, Xiuqin Zhao, Weitao Song, Annie Z. Luo, Rama D. Gangula, Kevin M. Slawin and David M. Spencer. (2005) Versatile prostate cancer treatment with inducible caspase and interleukin-12, Cancer Research, 65 (10), 4309-4319.
  • Seethammagari, M., Xie, X., Greenberg, N.M., and Spencer, D.M. (2006) EZC2-Prostate offer both high-sensitivity and specificity for non-invasive imaging of prostate cancer progression and androgen receptor action. Cancer Res. 66, 6199-209.
  • Park, D., Lapteva, N., Seethamagari, M., Slawin, K.M., Spencer, D.M. (2006) An essential role for Akt1 in dendritic cell function and tumor immunotherapy, Nature Biotechnology, 24, 1581-90.
  • Lapteva, N., Seethammagari, M.R., Hanks, B.A., Jiang, J., Levitt, J.M., Slawin, K.M., and Spencer, D.M. (2007) Enhanced activation of Human Dendritic Cells by Inducible CD40 and TLR4 Ligation, Cancer Res, 67, 10528-37.
  • Acevedo,V.D., Gangula, R.D., Ayala, G., Peterson, L., Ittmann, M., and Spencer, D.M. (2007) Inducible FGFR-1 leads to Irreversible Prostate Adenocarcinoma and an Epithelial to Mesenchymal Transition. Cancer Cell, 12, 559-71.

    Contact Information:
      David M. Spencer, Ph.D.
      Department of Pathology & Immunology
      Baylor College of Medicine
      One Baylor Plaza, BCM245
      Houston, Texas 77030, U.S.A.
    Telephone: 713-798-6475
    Fax: 713-798-3033
    E-mail: dspencer@bcm.edu

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