In most tissues, including the central nervous system, differentiation from a somatic multipotent stem cell proceeds through transit-amplifying progenitors (TAPs). These highly mitotic progenitors are the first committed cells, which may remain multipotent, but have limited self-renewal capacity. Despite the recent progress in understanding the pathways operating in stem cells, the molecular mechanisms that function selectively in TAPs remain poorly studied. TAPs are likely critical cells that determine the extent of adult neural cell growth. TAPs may also be the key cells responsible for the transition from lifetime self-renewing stem cells to highly proliferative but short-lived progenitors. This is a very important point in neural cell development and thus, TAPs may be potential targets for neoplastic transformations. We have identified a novel protein (MELK) as a functional marker of proliferating cells in the adult brain. MELK is likely to selectively modulate stem-to-progenitor cell transition and proliferation of TAPs. On the other hand MELK has emerged as a promising target for many types of cancer, in particular glioblastomas. An important difference between normal neural progenitors and CD133+ cancer stem cells is that MELK will inhibit growth in normal neural progenitors but will kill cancer stem cells. However, nothing is known about the role of MELK in vivo.. The goal of this proposal is to address this critical issue.
Our hypothesis is that MELK is upregulated in neural progenitors in vivo but its function is not needed for survival of normal TAPs. We also suggest that MELK activity in cancer stem cells is required for brain tumor survival and growth.
Our Aims are to determine the exact areas of MELK expression and its activity in the central nervous system using mouse models. We will also determine whether MELK acitivity is required for tumor formation in the mouse. . Finally, we will test whether MELK inhibitors kill primary human glioblastomas.
My laboratory generated a diverse set of reagents such as genetically modified mice and efficient tools to manipulate the MELK gene. In collaboration with Dr. Abagyan (Scripps) we have produced molecules that inhibit MELK expression and we established a partnership with the neurosurgeon Dr. Jandial (UCSD) to obtain primary glioblastoimas. Thus, my laboratory is uniquely positioned to address the role of MELK in neural progenitors under normal conditions and evaluate the its potential as target for anti-tumor drug development for primary human brain tumors.
Understanding the exact role of MELK and its mechanism of action will allow manipulation of neural progenitor compartment for therapeutic purposes. On the other hand the different sensitivity to MELK inhibition seen in normal TAPs and glioblastomas makes it a perfect target for treatment of brain tumors.
Cell therapies proposed for traumatic CNS injuries, ischemia and several neurodegeneration conditions such as Parkinson’s, Alzheimer’s and ALS rely on our ability to manipulate neural stem and progenitor cells. Their therapeutic use depends on our understanding of the genes and pathways that govern proliferation of multipotent stem cells and progenitors as well as their differentiation under the appropriate stimuli. At the same time, it became clear that many tumors arise from the stem/progenitor cell compartments and the notion of cancer stem cells has been proposed to better characterize the cellular and molecular mechanism of tumor initiation and progression. It is now increasingly evident that the same genes and pathways are operating in both normal and cancer stem cells. However, the lack of fundamental knowledge in this area impedes technological advancements.
The PI’s laboratory has recently identified Maternal Leucine Zipper Kinase (MELK) as a key candidate gene that modulates proliferation of both normal neural progenitors and malignant cancer stem cells in human glioblastomas and we have developed several lead small molecule inhibitors of MELK function. Our analysis will unequivocally determine the in vitro role of MELK in both normal neurogenesis and growth of primary glioblastomas.
Here we will use a mouse model of malignant glioma that mimics common genetic lesions underlying primary glioblastoma in humans. Moreover, we will test whether small molecule inhibitors of MELK kill primary glioblastomas.
Our hypothesis is that MELK regulates neural progenitors within the adult germinal zones in vivo. If this is correct the agonist of MELK function will increase adult neurogenesis and, likely, will result in benefits currently associated with treatments such as Prozac. If MELK is also indispensable for brain tumor growth, small molecule inhibitors of MELK will lead to a major clinical breakthrough in treatment of malignant brain tumors.
An effective, straightforward, and understandable way to describe the benefits to the citizens of the State of California that will flow from the stem cell research we propose to conduct is to couch it in the familiar business concept of “Return on Investment”. The novel therapies that will be developed as a result of our research program and the many related programs that will follow will provide direct benefits to the health of California citizens. These financial benefits will derive directly from two sources. The first source will be the sale and licensing of the intellectual property rights that will go to the state and its citizens from stem cell research programs financed by the CIRM. The second source will be several types of tax revenues that will be generated from the increased bio-science and bio-manufacturing businesses that will be attracted to California by the success of the CIRM.