Description:

Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder in which patients often develop multiple lesions, including slow growing spinal cord schwannomas and cutaneous schwannomas in the periphery, and meningiomas and gliomas in the brain and spine. Although usually benign and focal schwannomas and meningiomas associated with NF2 can severely compromise neural function leading to paralysis, deafness, and death through compression of critical brain nerves and structures, or blockade of CSF flow. In NF2, the most severe and life-threatening tumors are cranial nerve schwannomas and meningiomas at the skull base, which due to their size or multiplicity, are not surgically accessible. Repeated resection of tumor material can leave patients with multiple neurologic deficits, further loss of nerve function, and so debilitated that further surgery is not helpful. Thus, it is our hope to find a novel pharmacological drug which effectively reduces tumor growth as an alternative to surgery.

NF2 is caused primarily by dysfunction of the NF2 gene product called merlin which inhibits directly PAK1, a Rac/ CDC42-dependent Ser/Thr kinase. In collaboration with Dr. Hiroshi Maruta at the Hamburg University Hospital (UKE) in Germany, we are screening a number of pharmacological inhibitors of PAK1 in a murine xenograft model for NF2. Tumors are formed from subcutaneous implantation of a schwannoma cell line into the flanks of immunodeficient mice. It is our objective to find a PAK1 inhibitor which reduces the growth of schwannomas in our NF2 mouse model. This drug(s) will have tremendous clinical implications for the future, particularly if it could be used in place of invasive surgery, which often leaves patients debilitated.

The resources of NCRR BRC used for this project include the tissue culture room, laboratory, and office space. Funding for this project include the NF CURE award to S. M. M. from NF CURE JAPAN, and a grant from the Peterson Foundation to support the research of S. M. M. This work was presented at the NF Conference sponsored by the Children’s Tumor Foundation in June, 2007 in Park City, Utah.

We previously demonstrated that PAK1 is essential for the growth of both NF1 and NF2 tumors. Thus, several anti-PAK1 drugs including FK228 and CEP-1347 are being developed for the treatment of NF tumors. However, so far no effective NF therapeutics is available in the market. Since propolis, a very safe healthcare product from bee-hives, contains anti-cancer ingredients called CAPE (caffeic acid phenethyl ester) or ARC (Artepillin C), depending on the sources, both of which block the oncogenic PAK1 signaling pathways, we have explored its potential therapeutic effect on NF tumors in vivo. Here we demonstrate that Bio 30, a CAPE-rich water-miscible extract of New Zealand (NZ) propolis suppresses completely the growth of human NF1 cancer called MPNST (malignant peripheral nerve sheath tumor), and causes an almost complete regression of human NF2 tumor (Schwannoma), both grafted in nude mice. Although CAPE alone has never been clinically used, due to its poor bioavailability/water-solubility, Bio 30 contains a plenty of lipids which solubilizes CAPE, and also includes several other anti-cancer ingredients that seem to act synergistically with CAPE. Thus, it would be worth testing clinically if Bio 30 and other CAPE-rich propolis are useful for the treatment of NF patients.
There are mainly three types of propolis whose major anti-cancer ingredients are entirely different: 1) CAPE (caffeic acid phenethyl ester)-based propolis in Europe, Far East, and New Zealand, 2) Artepillin C (ARC)-based Brazilian green propolis, and 3) Brazilian red propolis. We have shown previously that NF (neurofibromatosis)-associated tumors require the kinase PAK1 for their growth, and that ARC suppresses angiogenesis, suggesting the possibility that ARC also blocks the oncogenicPAK1 signaling. Here we show for the first time that both ARC and the green propolis extract (GPE) indeed block the PAK1 signaling selectively, without affecting another kinase called AKT. Furthermore, we have confirmed that ARC as well as the GPE suppress almost completely the growth of human NF tumor xenografts in mice, as does Bio 30. These results suggest that both CAPE-based and ARC-based propolis extracts are natural anti-PAK1 remedies and would be among the first effective NF therapeutics available in the market. Since more than 70% of human cancers such as breast and prostate cancers require the kinase PAK1 for their growth, it is quite possible that the GPE would be potentially useful for the treatment of these cancers, as is Bio 30.