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Jayne M. Stommel, Ph.D.

Portait Photo of Jayne Stommel
Radiation Oncology Branch
Center for Cancer Research
National Cancer Institute
Building 10, Room B3B69D
Bethesda, MD 20892
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Dr. Stommel received her B.S. Magna cum Laude with College Honors in Cell and Molecular Biology from the University of Washington in Seattle. She received a Ph.D. from the University of California, San Diego with Dr. Geoffrey Wahl at The Salk Institute for Biological Studies in La Jolla. Her Ph.D. thesis work examined the molecular interactions of p53 and MDM2 and was funded by an NSF Graduate Research Fellowship. She then trained as a post-doc under Dr. Ronald DePinho at the Dana-Farber Cancer Institute/Harvard Medical School in Boston, focusing on Receptor Tyrosine Kinase signaling in Glioblastoma Multiforme and Colorectal Cancer. Her post-doctoral work was funded by an American Brain Tumor Association Fellowship, a Ruth L. Kirschstein National Research Service Award (NRSA), a DFCI/Harvard Cancer Center Gastrointestinal SPORE Career Development Award, and an NIH Pathway to Independence (PI) Award (K99/R00). Dr. Stommel joined the NCI as a Tenure-Track Investigator in September 2010.


Oncogenic Kinase Signaling in Glioblastoma Multiforme

  • Rationale:

  • The development and viability of multicellular organisms depends on cells correctly 'knowing' when to live or die, to divide or arrest, and to move or stay put. Cancer cells usurp the processes by which normal cells know their individual roles within an organism, aberrantly surviving, dividing, and invading surrounding tissues by hijacking the normal cellular controls on these processes. Receptor tyrosine kinases, or RTKs, are membrane-bound signaling proteins that relay growth and environmental cues from outside the cell inward via a phosphorylation and protein-protein association cascade that ultimately results in cell survival, division, and migration. Consequently, RTKs are frequently misappropriated by cancer cells to instigate and sustain primary and metastatic tumor growth.

    The relative ease with which RTKs can be inhibited pharmacologically has made this protein family an attractive target for cancer therapy. However, despite the demonstrated importance of RTK signaling in the majority of human cancers, the clinical success of RTK inhibitors has thus far been limited to the small minority of tumors with strongly-activating RTK mutations that render them 'addicted' to their growth-promoting effects. Unfortunately, recent cancer genome sequencing efforts have revealed that few tumors fit this category: rather, the growth of most tumors is likely to be driven by many different less-potent and infrequent mutational events that activate complex combinations of signaling networks. Moreover, the inhibition of well-known RTK downstream effectors, such as Akt, MAPK, and mTOR, have yielded only incremental increases in patient survival or have revealed the existence of previously unknown feedback loops that complicate their use as therapeutic agents. Together, these observations suggest that RTKs sit at the apex of a highly-complicated and poorly-understood network of signaling molecules that conspire to promote tumor growth through myriad cellular processes. Because a thorough understanding of these networks will be critical to design effective combinatorial treatments for primary and metastatic tumors, my lab studies the complexity of RTK signaling networks in cancer, with the ultimate goal of developing novel therapies that target these pathways.

  • Background:

  • Dr. Stommel began studying RTK signaling networks during her post-doctoral fellowship in the laboratory of Dr. Ronald DePinho, where she investigated why EGFR inhibitors fail to treat the most common and deadly form of brain tumor, Glioblastoma Multiforme (GBM). GBM is among the most lethal human cancers: despite decades of study and advances in standard-of-care cytotoxic and radiation therapies, the median survival upon diagnosis remains a dismal fifteen months. Consequently, agents that specifically target the molecular lesions that drive the initiation and maintenance of this tumor are desperately needed. The RTK EGFR is amplified and/or mutated in about 40% of GBMs and numerous studies have demonstrated an important role for this kinase in driving glioma cell growth in vitro and in vivo. However, EGFR inhibitors that have successfully reduced the growth of other tumors have had little impact on this disease.

    Drs. Stommel and DePinho found that a possible explanation for the failure of EGFR inhibitors to durably treat GBM is because these tumors do not have any single RTK that orchestrates oncogenic signaling - on the contrary, nearly every tumor and cell line had unique combinations of activated RTKs that together promoted cell survival and transformation. Importantly, these RTKs were predominantly activated via unknown processes and only rarely by mutation or genomic alteration. They also observed that cell growth and oncogenic signaling were not fully abrogated until the majority of the profiled activated RTKs were inhibited, a finding that is consistent with the failure of RTK inhibitor monotherapy to successfully reduce tumor growth in GBM patients. Biochemically, they found that RTKs could swap places with one another in activated signaling complexes and provide additive signaling inputs to activate canonical oncogenic pathways. These observations imply a promiscuity in RTK signaling that has grave implications for the acquisition of resistance to targeted RTK inhibitors.

  • Projects:

  • Project 1: Mechanistic investigation of the RTK cooperation paradigm in vitro and in vivo.
    Dr. Stommel's post-doctoral work suggests two possible explanations for why cancer cells might need to co-activate multiple RTKs. First, she found that activated RTKs additively contribute to cell growth and downstream signaling, such that the genetic or pharmacological inhibition of any individual RTK only partially blocks these functions. Second, she found that RTKs can replace one another in signaling complexes to maintain oncogenic signaling when a particular RTK is lost. Both these observations suggest that the individual identities of activated RTKs might not be as important for tumor growth as meeting a threshold of signaling with a minimum number of RTKs. In contrast, another explanation for why cancer cells might need multiple co-activated RTKs is that each RTK makes a separate contribution to tumor physiology: for example, perhaps one RTK promotes angiogenesis, another cell survival, and a third cell movement. To distinguish between these possibilities, we are addressing the impact of combinatorial RTK signaling on cellular transformation, malignant phenotypes, and downstream signaling using the following approaches: 1) examining the effects of RTK co-expression on the growth of immortalized normal human astrocytes and tumor neurospheres in culture and in a mouse orthotopic brain tumor system and 2) performing genetic screens to identify classes of cooperating RTKs.

    Project 2: RTK effector gene discovery.
    One mechanism by which activated RTKs might cooperatively contribute to tumor cell survival is by engaging overlapping downstream effectors. If this were true, then the inhibition of any one RTK pathway would be insufficient to negate the effector due to inputs from the remaining activated RTKs. Because our data show that the spectrum of co-activated RTKs in tumors varies considerably from patient-to-patient, targeting these node effectors might be a more tenable therapeutic alternative to inhibiting RTKs. Moreover, the identification of these downstream effectors should reveal important novel mechanisms whereby RTKs confer their downstream effects. Our lab is identifying these convergent effectors and characterizing their modes of action through phospho-proteomic profiling, genetic and pharmacogenetic screens, in silico network analyses, and in vivo intracranial tumor generation.

    This page was last updated on 3/31/2014.