Photo of James Orth

James Orth

Associate Research Professor
303.492.5057
James.Orth@Colorado.EDU
Gold room A216
Explore James Orth's areas of research and more in Vivo
ORCID

Education

Post-doctoral Fellow, Harvard Medical School, 2005-2012
PhD, Mayo Clinic College of Medicine, 1999-2005

Biography

Research Interests:
The molecular, cellular and tissue basis of cancer chemotherapy

Research Profile:
In the case of a cancer cell, we now know that its growth, death, and metastatic potential are profoundly influenced by interactions with its neighbors and environment. However, this insight has had little impact on cancer pharmacology. Most drug discovery and development still proceeds on the assumption that the cancer cell can be considered in isolation from the tumor environment. My work questions this assumption.

To help improve cancer chemotherapy the laboratory is focused on the following paradigm:

 

Photo

 

Single-cell response, bystander effects, and tumor environment during drug response
Taxol is a main-line 'anti-mitotic' drug for breast and other cancers, but how it elicits a strong death response, particularly in vivo, and why some tumors respond well while others of the same type do not, are unclear. A potential mechanism to explain response variability is bystander effects that can act directly (e.g. cell-to-cell) or indirectly (e.g. tumor environment). Radiation-induced bystander effects are well documented, but drug-induced bystander effects are not. Microscopy of culture models and in vivo microscopy (IVM) of xenograft tumors, consisting of drug-sensitive and -resistant reporter cell lines, will be used to monitor single-cells and identify bystander effects after taxol and other drug treatment(s). The role of single-cell responses in bystander effects will be evaluated further using genetic and pharmacological perturbations. The complex role of tumor environment and its relationship to single cell response and bystander effects will also be studied. Collectively, these experiments will help explain the proliferation paradox, where a relatively slow growing tumor responds strongly to a drug that targets cell growth.

Drug-induced senescence as anti-cancer therapy
Senescent cells are common in many cancers, including pancreatic cancers, and represent a significant challenge but also an important therapeutic opportunity, because these cells support overall tumor growth, promote metastasis, and are a potential mechanism of acquired drug-resistance. Senescence is often dependent on the tumor suppressor p53, yet p53 is defective in many cancers. To harvest the potential of senescence as a therapy, it will be important to induce and target it specifically in cancer cells, independently of p53 status. Drug candidates that induce senescence specifically in cancer cells, and candidates that kill senescent cells obtained by pre-treatment with taxol and other anti-cancer drugs, will be identified and studied.

Targeting the cell cycle
The proliferation paradox will be directly tested in culture models and using IVM. Fluorescent cells or xenografts expressing fluorescent cell cycle markers will be used. Cells/tumors will be treated with different drugs thought to target G1-, S- and G2-phase, and mitosis. Cell cycle distribution and cell death for the different drugs will be studied. To further evaluate the proliferation paradox, the cell cycle will be manipulated using drugs that result in cell cycle accumulation in specific stages followed by treatment with additional drugs. For example, platinum drugs that induce DNA damage and cell cycle arrest, often in S-phase, are sometimes effectively combined with taxol, but the role of cell cycle in this combination and how it relates to cell death and tumor response are unclear. Small-molecule screening and cell profiling technologies will also be employed.

Selected Publications

Prolonged mitotic arrest triggers partial activation of apoptosis, resulting in DNA damage and p53 induction.*
Orth JD, Loewer A, Lahav G, Mitchison TJ. Mol Biol Cell. 2012 Feb 15;23(4)567-76.
*Featured March 5, 2012 on: http://highmagblog.blogspot.com.

Rapid induction of apoptosis during Kinesin-5 inhibitor-induced mitotic arrest in HL60 cells.
Tang Y, Orth JD, Xie T, Mitchison, TJ. Cancer Lett. 2011 Nov 1;310:15-24.

Analysis of mitosis and anti-mitotic drug responses in tumors by in vivo microscopy and single-cell pharmacodynamics.
Orth JD, Kohler RH, Foijer F, Sorger PK, Weissleder R, Mitchison TJ. Cancer Res. 2011 Jul 1;71(13):4698-16.

Cell death when the SAC is out of commission.
Huang HC, Shi J, Orth JD, Mitchison TJ. Cell Cycle. 2010 Jun 25;9(11):2049-50.

An intermittent live cell imaging screen for siRNA enhancers and suppressors of a kinesin-5 inhibitor.
Tsui M, Xie T, Orth JD, Carpenter AE, Rudnicki S, Kim S, Shamu CE, Mitchison TJ. PLoS One. 2009 Oct 5;4(10):e7339.

Evidence that Mitotic Exit Is a Better Cancer Therapeutic Target Than Spindle Assembly.*
Huang HC, Shi J, Orth JD, Mitchison TJ. Cancer Cell. 2009 Oct 6;16(4):347-58.
*Comment in: Cancer Cell. 2009 Oct 6;16(4):274-5.

Quantitative live imaging of cancer and normal cells treated with Kinesin-5 inhibitors indicates significant differences in phenotypic responses and cell fate.*
Orth JD, Tang Y, Shi J, Loy CT, Amendt C, Wilm C, Zenke FT, Mitchison TJ. Mol Cancer Ther. 2008 Nov;7(11):3480-9.
* Cover article.

Cell type variation in responses to antimitotic drugs that target microtubules and kinesin-5.
Shi J, Orth JD, Mitchison T. Cancer Res. 2008 May 1;68(9):3269-76.