The Lankenau Institute for Medical Research
Association: Resident Faculty
Awards and Honors
Dr. Alexander Muller is exploring fundamental molecular and genetic interactions that exist between tumors and the host environment as the basis for developing novel approaches for achieving effective therapeutic intervention. In one project, Dr. Muller is investigating a key mechanism that facilitates tumor outgrowth by redirecting the immune system to ignore or even support cancer development rather than acting to suppress it. The enzyme involved, called IDO, normally has an important role in protecting the developing fetus from the mother’s immune system. Dr. Muller’s research has been at the forefront of the rapidly developing conceptual paradigm that targeting immune regulatory mechanisms such as IDO can be an effective strategy for improving the antitumor responses achieved with standard chemotherapeutic drugs. Most recently, Dr. Muller and colleagues have published the first sound genetic demonstration of IDO’s importance in promoting tumor progression in mouse models of lung cancer and metastasis. Furthermore, they have uncovered surprising evidence of how remarkably broad the impact of IDO is on the fundamental external drivers of tumor development including inflammation, blood vessel development and immune escape.
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 become cancerous. 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.
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 generally 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 may be a particularly attractive point of vulnerability. Currently, Dr. Muller’s laboratory is focused on two projects that examine different aspects of tumor/host interactions. In collaboration with Dr. George Prendergast, his laboratory is studying the pro-tolerogenic enzyme IDO as a therapeutic target for the development of small molecule inhibitors (Project 1). Dr. Muller is 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).
Increased tryptophan catabolism by IDO has been associated with a broad spectrum of cancers and is implicated in the pathophysiological process of tumoral immune escape. We initially reported that IDO expression is negatively regulated by the Bin1 anti-cancer gene and that inhibiting the IDO enzyme can leverage the efficacy of cytotoxic chemotherapy. We have subsequently identified several different structural classes of IDO inhibitory compounds and confirmed their potential utility through in vitro and in vivo target validation studies. While it is now well established that IDO inhibitors can produce immune-based antitumor responses, how this occurs continues to be an area of active investigation. IDO has been suggested to be a means by which tumors might escape immune surveillance. However, in the context of the classical DMBA/TPA skin carcinogenesis model, Dr. Muller’s laboratory found IDO to be induced by the inflammatory tumor-promoting process itself, independent of tumor immunoediting. Furthermore, loss of IDO did not exacerbate the severity of inflammation as might be expected if it were simply immunosuppressive. Rather, IDO appears to be integrally involved in shaping the inflammatory environment to support tumor outgrowth. Intriguingly, in patients with rheumatoid arthritis or lupus, elevated tryptophan degradation has been correlated with disease activity, suggesting the possibility that IDO might also play a role in promoting inflammatory, autoimmune pathologies. Consistent with this idea, collaborative studies with Dr. Laura Mandik-Nayak at LIMR in a spontaneous mouse model of arthritis, found IDO to be elevated at the onset of disease, while treatment with the IDO pathway inhibitor 1-methyl-tryptophan significantly reduced disease severity. These findings add to a growing body of evidence suggesting that IDO is a key element shaping the pathogenic nature of the chronic inflammatory environment.
In recent studies, Dr. Muller’s laboratory has reported that IDO-deficient mice are resistant to both KRAS-induced lung adenocarcinomas and pulmonary breast carcinoma metastases. Unexpectedly, blood vessel density was significantly diminished in the lungs of Ido1-nullizygous mice. Elevation of the inflammatory cytokine IL6, which was associated with tumor outgrowth in the lungs in both models, was greatly attenuated with the loss of Ido1, consistent with in vitro evidence that IDO activity markedly potentiates IL6 production. MDSCs (myeloid derived suppressor cells) exhibited reduced T cell suppressive activity when isolated from tumor-bearing, IDO-deficient animals that could be rescued by ectopic production of IL6 in the tumor. IL6 production could likewise reverse the pulmonary metastasis resistance exhibited by IDO-deficient mice. These findings fill a conspicuous gap by providing fundamental genetic proof of concept for IDO as a therapeutic target. Furthermore, the interpretation that IDO acts as an integrative immune modifier linking inflammation, vascularization and immune escape to promote the establishment of a pathogenic, tumor-promoting environment represents a major conceptual breakthrough regarding IDO’s role in cancer. This work has been supported by grants to Dr. Muller from the DOD Breast Cancer Research Program and from the Concern and W.W. Smith Foundations and is currently being supported by a grant from Susan G. Komen for the Cure. Dr. Muller is also a Co-Investigator on NIH-funded consortium grants between LIMR and Bryn Mawr College to develop pharmacologically superior IDO inhibitors and between LIMR and Thomas Jefferson University to study the role of the related enzyme IDO2 in pancreatic cancer.
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. Dr. Muller has identified 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 medial portion of chromosome 13 and Dr. Muller was the recipient of a grant from the Lance Armstrong Foundation to continue these investigations into the underlying genetic basis for testicular tumor susceptibility.
Dr. Muller's Google Scholar page
IDO2 Modulates T Cell-Dependent Autoimmune Responses through a B Cell-Intrinsic Mechanism.
Merlo LM, DuHadaway JB, Grabler S, Prendergast GC, Muller AJ, Mandik-Nayak L. J Immunol. 2016 Jun 1;196(11):4487-97.
O-alkylhydroxylamines as rationally-designed mechanism-based inhibitors of indoleamine 2,3-dioxygenase-1. Malachowski WP, Winters M, DuHadaway JB, Lewis-Ballester A, Badir S, Wai J, Rahman M, Sheikh E, LaLonde JM, Yeh SR, Prendergast GC, Muller AJ. Eur J Med Chem. 2016 Jan 27;108:564-76.
Cardiac-Specific Disruption of Bin1 in Mice Enables a Model of Stress- and Age-Associated Dilated Cardiomyopathy. Laury-Kleintop LD, Mulgrew JR, Heletz I, Nedelcoviciu RA, Chang MY, Harris DM, Koch WJ, Schneider MD, Muller AJ, Prendergast GC. J Cell Biochem. 2015 Nov;116(11):2541-51.
Pigott E, Duhadaway JB, Muller AJ, Gilmour S, Prendergast GC, Mandik-Nayak L. 1-Methyl-tryptophan synergizes with methotrexate to alleviate arthritis in a mouse model of arthritis. Autoimmunity. 47(6):409-18, 2014.
Prendergast GC, Smith C, Thomas S, Mandik-Nayak L, Laury-Kleintop LD, Metz R, and Muller AJ. Indoleamine 2,3-dioxygenase pathways in pathogenic inflammation and immune escape in cancer. Cancer Immunol. Immunother. 63(7):721-35, 2014
Metz R, Smith C, Duhadaway JB, Chandler P, Baban B, Merlo LM, Pigott E, Keough MP, Rust S, Mellor AL, Mandik-Nayak L, J Muller A, Prendergast GC. IDO2 is critical for IDO1-mediated T cell regulation and exerts a non-redundant function in inflammation. Int Immunol. 26(7):357-67, 2014