Alexander J. Muller , PhD

Lay Description:

Dr. Alexander Muller is exploring fundamental molecular and genetic interactions that exist between tumors and the host environment that may provide unique inroads for therapeutic intervention. In one project, Dr. Muller investigates how malignant cells send signals to modify their environment to overcome the immune defense mechanisms that normally detect and kill cancer cells. Dr. Muller and colleagues have identified a process whereby cancer cells activate an enzyme called IDO (indoleamine 2, 3-dioxygenase) to avoid destruction by inhibiting immune rejection. IDO has been shown to protect a fetus from being rejected by its mother. Dr. Muller’s ongoing research focuses on defining how tumors utilize the immunosuppressive enzyme IDO to defeat the immune system and how this mechanism can be inhibited to develop better cancer treatments.

In a second project, Dr. Muller is investigating the genetic basis for how the normal growth of stem cells can go awry, leading them to form tumors. At a time when stem cell therapies hold the promise to treat a wide range of diseases, a key concern arises that these cells may also form tumors. Therefore, it is essential to better understand the mechanisms that can transform normally useful stem cells into cancer cells.
 
Dr. Muller’s work has led to the first clinical testing of an IDO-inhibitory drug in cancer patients and is opening new avenues to improved cancer treatment. Dr. Muller’s research is also uncovering new ways to limit the danger of cancer formation within the therapeutic context of future stem cell therapies.

Scientific Description:

The traditional goal of chemotherapy has been to directly kill any residual tumor that cannot be surgically removed. However, the effectiveness of this approach is limited by the inherent nature of the cancer cells. Being of host origin, cancer cells are particularly difficult targets for the development of cytotoxic agents that are sufficiently selective to avoid severe side effects in patients, and the therapeutic window for such agents is usually narrow. Tumors are also remarkably resilient in their ability to rebound from such treatments. Even when the vast majority of cancer cells are killed by a cytotoxic agent, a small number of residual cells can be sufficient to seed the regrowth of a tumor. Furthermore, as a consequence of the genetic plasticity that is characteristic of cancer cells, the regrown tumor may no longer respond the previously successful therapy, having developed resistance in response to selective pressure. Thus, successful cancer treatment may require multiple agents targeting different mechanisms similar to the approach used against highly mutable infectious agents such as HIV. Because tumors are absolutely dependent on interactions with the host for their growth and survival, the host/tumor interface might be a particularly attractive point of vulnerability. Currently, my laboratory is focused on two projects that examine different aspects of tumor/host interactions. We are studying, in collaboration with Dr. George Prendergast, the pro-toleragenic enzyme indoleamine 2,3-dioxygenase (IDO) that we reported on as a potential therapeutic target for the development of small molecule inhibitors (Project 1). We are also independently pursuing studies to determine the molecular basis for increased male germ cell tumor susceptibility in 129 strain mice mapped to the Pgct1 locus (Project 2).

1) IDO-mediated tumoral immune tolerance: A potential target for small molecule inhibitors.
Tumors benefit greatly from a local inflammatory environment but must escape immune-mediated rejection in order to progress successfully. The IDO enzyme suppresses T cell activation and promotes immunological tolerance by catalyzing the breakdown of the essential amino acid tryptophan. The physiological relevance of IDO was first established with the demonstration that maternal immune rejection of allogeneic mouse concepti can be elicited through administration of the IDO inhibitory compound 1-methyl-tryptophan (1MT). Increased IDO activity has been associated with a broad spectrum of cancers and is implicated in the pathophysiological process of tumoral immune escape. We have reported that IDO expression is negatively regulated by Bin1, an anti-cancer gene that is lost or attenuated during tumor progression. Using 1MT as a proof of principle compound in transgenic MMTV-Neu mice, we have shown that inhibiting the IDO enzyme can leverage the efficacy of cytotoxic chemotherapy in this autochthonous breast cancer model. Further preclinical evaluation of 1MT has indicated that the D and L stereoisomers show marked cell type variation in their ability to inhibit IDO activity with clear biological consequences. We have also identified the natural product brassinin, a plant phytoalexin with known chemopreventative properties, as a competitive inhibitor of IDO. Derivatization around the brassinin core structure has led to the identification of more potent compounds, providing the basis for structure activity relationship analysis that will inform future IDO inhibitor development.

2) Male primordial germ cell tumor susceptibility: tipping the balance between normal and neoplastic.
Primordial germ cells exhibit unique characteristics that may make them particularly pertinent for understanding fundamental aspects of tumor development. During early embryogenesis, the primordial germ cell population expands rapidly and actively migrates from the base of the allantois to colonize the gonadal anlagen. Like tumor cells, these cells are actively proliferating, motile, and invasive. Furthermore, these cells form tumors (teratomas or teratocarcinomas) when transplanted to an ectopic site in an adult host. Reciprocally, embryonal carcinoma cells, which are the undifferentiated component of primordial germ cell tumors, often retain some degree of normal differentiative capacity. This is most dramatically demonstrated by the ability of some embryonal carcinoma cell lines to contribute to the development of a chimeric mouse when implanted into a developing blastocyst. The same genetic programs that underlie the neoplastic potential of primordial germ cells might very well be appropriated by somatic tumors as they become progressively malignant. Thus primordial germ cell tumors may prove to be a fundamental model system for understanding the genetic basis of other cancers. Male mice of the 129 strain background are predisposed to developing spontaneous primordial germ cell tumors, and determining the genetic basis for this predisposition should provide insight into how the neoplastic potential of primordial germ cells is normally kept in check. We have previously reported the identification of a genetic locus, Pgct1, that is strongly associated with the primordial germ cell tumor predisposition of 129 strain male mice. The Pgct1 locus was mapped with a high degree of significance to the proximal portion of chromosome 13. Data recently made available from the sequencing of the mouse genome should facilitate the search for the susceptibility gene at this locus.

Selected Publications:

1. Muller, AJ, L Mandik-Nayak, & GC Prendergast. Beyond immunosuppression: reconsidering IDO as a pathogenic element of chronic inflammation. Immunotherapy 2(3):293-7 (2010). 
2. Metz, R, J DuHadaway, S Rust, DH Munn, AJ Muller, M Mautino & GC Prendergast. Zinc protoporphyrin-IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Mol. Cancer Ther. 9(6):1864-71 (2010). 
3. Prendergast GC, R Metz, & AJ Muller Towards a genetic definition of cancer-associated inflammation. Am. J. Pathol. 176(5):2082-7 (2010). 
4. Muller AJ, DuHadaway JB, Jaller D, Curtis P, Metz R, Prendergast GC. Immunotherapeutic suppression of indoleamine 2,3-dioxygenase and tumor growth with ethyl pyruvate. Cancer Res. 2010 Mar 1;70(5):1845-53. Epub 2010 Feb 16. 
5. Scott, G.N., J. DuHadaway, E. Pigott, N. Ridge, G.C. Prendergast, A.J. Muller and L. Mandik-Nayak. The immunoregulatory enzyme IDO paradoxically drives B cell-mediated autoimmunity. J. Immunol. 182:7509-7517 (2009).
6. Witkiewicz AK, CL Costantino, R Metz, AJ Muller, GC Prendergast, CJ Yeo & JR Brody. Genotyping and expression analysis of IDO2 in human pancreatic cancer: a novel, active target. J Am Coll Surg. 208(5):781-7 (2009). 
7. Muller, A.J., M.D. Sharma, P.R. Chandler, J.B. DuHadaway, M.E. Everhart, B.A. Johnson III, D.J. Kahler, J. Pihkala, A.P. Soler, D.H. Munn, G.C. Prendergast, A.L. Mellor. Chronic inflammation that facilitates tumor progression creates local immune suppression by inducing indoleamine 2,3 dioxygenase. Proc. Natl. Acad. Sci. 105:17073-8 (2008).
8. Kumar S, Malachowski WP, DuHadaway JB, LaLonde JM, Carroll PJ, Jaller D, Metz R, Prendergast GC, Muller AJ. Indoleamine 2,3-dioxygenase is the anticancer target for a novel series of potent naphthoquinone-based inhibitors. J Med Chem. 2008 Mar 27;51(6):1706-18. Epub 2008 Mar 5.
9. Banerjee T, Duhadaway JB, Gaspari P, Sutanto-Ward E, Munn DH, Mellor AL, Malachowski WP, Prendergast GC, Muller AJ. A key in vivo antitumor mechanism of action of natural product-based brassinins is inhibition of indoleamine 2,3-dioxygenase. Oncogene. 2008 May 1;27(20):2851-7. Epub 2007 Nov 19.
10. Hou DY, Muller AJ, Sharma MD, DuHadaway J, Banerjee T, Johnson M, Mellor AL, Prendergast GC, Munn DH. Inhibition of indoleamine 2,3-dioxygenase in dendritic cells by stereoisomers of 1-methyl-tryptophan correlates with antitumor responses. Cancer Res. 2007 Jan 15;67(2):792-801. 
11. Muller, A.J. and P.A. Scherle. Targeting the mechanisms of tumoral immune tolerance with small molecule inhibitors. Nat. Rev. Cancer 6:613 (2006).
12. Gaspari, P., T. Banerjee, W.P. Malachowski, A.J. Muller, G.C. Prendergast, J. DuHadaway, S. Bennett and A.M. Donovan. Structure-activity study of brassinin derivatives as indoleamine 2,3-dioxygenase inhibitors. J. Med. Chem. 49:684-692 (2006). 
13. Malachowski, W.P., R. Metz, G.C. Prendergast, and A.J. Muller. A new cancer immunosuppression target: indoleamine 2,3-dioxygenase (IDO). A review of the IDO mechanism, inhibition and therapeutic application. Drugs of the Future 30:897 (2005).Muller, A.J. and G.C. Prendergast. Marrying immunotherapy with chemotherapy: Why say IDO? Cancer Res. 65:8065 (2005).
14. Muller, A.J., W.P. Malachowski, and G.C. Prendergast. IDO in cancer: Targeting pathological immune tolerance with small molecule inhibitors. Expert Opin. Ther. Targets 9:831-849 (2005). 
15. Muller, A.J., DuHadaway, J.B., Donover, P.S., Sutanto-Ward, E., and Prendergast, G.C. (2005). Inhibition of indoleamine 2,3-dioxygenase, a target of the cancer suppression gene Bin1, potentiates cancer chemotherapy. Nature Med. 11: 312-319.
16. Muller, A.J., J.F. Baker, J.B. DuHadaway, K. Ge, G.E. Farmer, P.S. Donover, R. Meade, R. Grzanna, C. Reid, A.H. Roach, and G.C. Prendergast. (2003). Targeted disruption of the murine Bin1/Amphiphysin II gene promotes embryonic cardiomyopathy but does not impair endocytic functions. Mol. Cell. Biol. 23: 4295-4306.
17. Muller, A.J. , A.K. Teresky, and A.J. Levine. (2000) A male germ cell tumor susceptibility determining locus, pgct1, identified on murine chromosome 13. Proc. Natl. Acad. Sci. 97: 8421-8426. 
18. Muller, A.J. , K.B. Heiden, A.K. Teresky, and A.J. Levine. (1999) Genetic mapping of the embryonal carcinoma transplantation resistance locus Gt(B6) to mouse Chromosome 8. Immunogenetics 49: 949-956. 
19. Pendergast, A.-M., A.J. Muller, M. H. Havlik, Y. Maru, and O.N. Witte. (1991). BCR sequences essential for transformation by the BCR/ABL oncogene bind to the ABL SH2 regulatory domain in a nonphosphotyrosine-dependent manner. Cell 66: 161-171.
20. Muller, A.J. , J.C. Young, A.-M. Pendergast, M. Pondell, N.R. Landau, D.R. Littman, and O.N. Witte. (1991). BCR first exon sequences specifically activate the BCR/ABL tyrosine kinase oncogene of Philadelphia chromosome positive human leukemias. Mol. Cell. Biol. 11: 1785-1792. 
21. Lugo, T.G., A.-M. Pendergast, A.J. Muller, and O.N. Witte. Tyrosine kinase activity and transforming potency of bcr-abl oncogene products. Science 247: 1079-1082 (1990).