Wei Du, Ph.D.
Associate Professor, The Ben May Department for Cancer Research, University of Chicago
Targeting Cancer Progenitor Cells to Prevent medulloblastoma
The long term objective of this research is to open up new avenues for the treatment or prevention of medulloblastomas. Medulloblastoma is the most common malignant brain tumor in children. Current treatment ofmedulloblastoma includes surgery, radiation, and systemic chemotherapy. These treatments result in relatively high cure rates for early stage medulloblastomas but much lower cure rates for advanced stage ones. Furthermore the current treatments often result in severe side effects. Therefore, novel approaches that prevent or limit the progression of medulloblastoma can significantly improve the treatment and survival of this cancer.
Cell proliferation is the process by which cell multiplies and is tightly controlled in normal tissues by growth factors, which are secreted proteins that control the proliferation of eells. However cancer cells often lost such control. Medulloblastomas are generally believed to develop from uncontrolled proliferation of a special type of cell called cerebellar granule neuron precursors (GNPs). l\ormally, the proliferation of GNPs is controlled by a particular growth factor called Hh. Hh has critical roles in the proliferation of Gl\Ps and in the n0n11al growth of cerebellum. Ptc I, a negative regulator of the Hh, has been found to be a tumor suppressor gene mutated in medulloblastomas. Children who have inherited one bad copy of the Ptc I gene have a very high chance ofdeveloping medulloblastoma during childhood. Interestingly mice that have one bad copy of the Ptc I gene also develop medulloblastoma spontaneously while n0n11al mice, which have two good copies of the Ptc I gene, do not. Therefore the mice with one bad copy of the Ptc I gene can be used as a model to study medulloblastoma development. Studying the development of medulloblastomas in animal models is essential for developing new ways of cancer treatment or prevention.
D type cyclins (CycDI, CycD2, and CycD3) are genes that are known to regulate cell proliferation in a lot ofdifferent cell types. The abundance of the CycD I and CycD2 proteins is regulated by the Hh signaling pathway during cerebellar development. We have found that inactivation of CycD1 blocks tumor progenitors from progressing to medulloblastoma,suggesting that drugs that inhibit the function of CycD I can potentially be used to prevent or treat medulloblastomas. However, as CycD I have several distinct activities, before one begins to screen for inhibitors of CycD I to treat medulloblastomas, it is important to detemline which of the several activities of CycD 1 an inhibitor should block. The Aim I of the proposal will usc a CycDlmutant that specifically disrupted one of the functions ofCycDl to detennine if the ability of CycD I to induce kinase activity is required for its function in medulloblastoma progression. In a previous sLUdy, it was shown that disruption of this particular function of CycD! blocked CycD I ‘s ability to promote breast cancer development.
Another important consideration for the possibility of inhibiting eyeD I in medulloblastoma treatment or prevention is the possible side effect. Our previous studies have found that eyeD! is required only for a short period oftime in early cerebellar development. Therefore, if inhibition of eycD 1 after the period when eycD I is required for normal cerebellum development can still prevent medulloblastoma formation, this will make inhibition ofeycD 1 a viable strategy for treatment or prevention ofmedulloblastoma, especially for high risk children. The Aim 2 of this proposal will directly test if inactivation of eycD I will prevent the tumor progenitor cells from progressing to medulloblastoma when CycD I inactivation is induced ailer the time that CycD I is nom1ally required for cerebellar development.
If successful, the proposed studies will potentially provide new avenues to prevent the development of medulloblastomas in high risk children and to complement the current treatment of medulloblastomas by limiting medulloblastoma progression. Furtheml0re, such a strategy to target the proliferation of tumor progenitors can potentially be applied to other types of cancers in the future.