Dr. Quave (Principal investigator) in collaboration with Co-investigators Dr. Jack Arbiser (Emory Dermatology) and Dr. Yuhong Du (Emory Chemical Biology Discovery Center) have received a $50,000 grant from the Winship Invest$ award, made possible through the Melanoma Innovation Fund, a philanthropic fund established at Emory’s Winship Cancer Institute by anonymous donors. The award is to support a 12 month research project entitled: “Development of a novel discovery platform for melanoma therapeutics”.
The specific aims of the project are described below:
Specific Aims
Melanoma claims the lives of 9,000 people in the United States each year, and this is in spite of advances in both surveillance and therapeutic approaches1. In particular, patients with Stage IV melanoma have a poor prognosis for survival, averaging just 8-10 months2. Some of the targeted therapeutic approaches include surgery, isolated limb perfusion/infusion, cryotherapy, radiation therapy, BRAF inhibition, and immunotherapy. Efforts involving conventional chemotherapy have not been effective in enhancing survival, but efforts to block signal transduction and/or enhance anti-tumor immune responses have been associated with survival benefit1,3. Ultimately, combination approaches pairing a chemical approach with an immune (host-targeted) approach could prove to be most effective. New chemical entities (NCEs) are needed to fuel such efforts.
We have established a one-of-a-kind natural product library composed of botanical and fungal extracts for use in drug discovery research efforts. The Quave Natural Product Library (QNPL) is highly unique in that the collection was built based on species used in traditional medicine for disorders of the skin and soft tissues (warts, abnormal growths, infections, wounds, etc.) and general human health applications. It is a highly biodiverse collection of >500 crude extracts (plus 100’s of characterized, refined fractions), currently represented by 202 plant and fungal species from 68 families. Screening of this collection has already resulted in the discovery of several novel inhibitors of bacterial biofilms4-6 and quorum sensing-mediated virulence pathways7,8. To date, the collection has never been tested for anti-cancer activity.
Furthermore, a recent (March 2016) plant collection effort was undertaken in Florida, in which plants used in Native American medicine for skin disease were targeted. Many of the 150 species collected on this expedition have never been evaluated for their potential bioactivity. The overall aim of this study is to prepare extracts from the new species collected, and together with extracts from the existing QNPL, subject them to a robust High Throughput Screening (HTS) platform to detect NCEs with activity against melanoma.
Our hypothesis is that novel chemical entity (NCE) inhibitors of melanoma can be identified in the QNPL for further development to improve therapeutic response to melanoma. Our approach is innovative in the following two significant ways: 1) We are focusing our drug discovery efforts on plant secondary metabolites, which have had a proven track record of success in cancer therapy (i.e. etoposide, vincristine, vinblastine, taxol, etc.), but yet remain an underexplored area for drug development; and 2) We are concentrating our search for NCEs on secondary metabolites derived from plants already in use in traditional medicine for treatment of skin and soft tissue diseases, including abnormal growths. Our specific aims are:
Aim 1: Develop a novel natural products library for deployment in the screening platform. Aqueous and organic extractions will be undertaken on 150 newly collected plant species. Extracts will be prepared for inclusion in the QNPL and loaded onto 384-well “master plates” for high throughput screening in Aim 2.
Aim 2: Evaluate extracts in the QNPL for activity against melanoma cell lines using high throughput screening technologies. HTS robotic platforms will be employed to screen extracts for anti-cancer activity using established cell viability and NF-kB translocation assays with the A375 melanoma cell line. Top confirmed positive hits with minimal toxicity to normal fibroblasts will be chemically characterized by HPLC and LC-FTMS for de-replication efforts to identify any known constituents by exact mass matches.
Additional Outcomes: In addition to obtaining preliminary data necessary for successful submission of external funding proposals focused on discovery and development of novel anti-melanoma therapies, this project will result in creation of a concrete product for use by other Emory Investigators. The QNPL developed for this project will be deposited with the HTS Emory Chemical Biology Discovery Center for use in other drug discovery initiatives for a variety of targets relevant to human health. This library is not commercially available, and represents a one-of-a-kind collection of plant secondary metabolites derived from species used in traditional medicinal applications, with great potential for discovery of NCEs.
