We are excited to announce that the Quave Research Group has secured $50,000 in funding from Winship Cancer Center at Emory University to pursue our drug discovery program for melanoma. The project, entitled “Isolation and Characterization of Novel Therapeutics Targeting Melanoma” will follow up on hit extracts we identified during an initial high throughput robotics screen of the Quave Natural Products Library. We will partner with the Emory Chemical Biology Discovery Center in these efforts. This project is made possible by the generous support of melanoma survivors and supporters of cancer research. Thank you!
Summary Project Description:
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 approaches. In particular, patients with Stage IV melanoma have a poor prognosis for survival, averaging just 8-10 months. 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 benefit. 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 leveraged the Quave Research Group’s one-of-a-kind natural product library composed of botanical and macro-fungal extracts for use in drug discovery research efforts for melanoma therapies. The Quave Natural Product Library (QNPL) is unique in that the collection has been built based on species used in traditional medicine (TM) for skin and skin structure infections (SSSI) and other forms of infectious and inflammatory disease. It is a highly biodiverse collection of >1,800 crude extracts (plus 100’s of characterized, refined fractions), currently represented by >600 plant and fungal species. Screening of this collection has already resulted in the discovery of several novel inhibitors of bacterial biofilms and quorum sensing-mediated virulence pathways. We have successfully identified four extracts with potent (IC50 < 8 µg/mL) and selective activity against melanoma cell line A375.
Our hypothesis is that potent (IC50 < 1 µg/mL) and selective (nontoxic to HaCATs and a panel of lung cancer cell lines) compounds can be isolated from these four hit extracts. Despite a rich history of successful anti-cancer drug discovery from botanical natural products (i.e. etoposide, vincristine, vinblastine, taxol, etc.), this remains an underexplored area for anticancer therapeutic discovery and development. Our approach is innovative in two significant ways: 1) We have focused our discovery efforts on plants collected in the Mediterranean basin – a global hotspot for plant diversity and high levels of endemism – which was not included in the NCIs collection efforts for the creation of their extensive natural products library. As a consequence of this, most of the species in the QNPL had never been screened against cancer targets; 2) We are concentrating our search on secondary metabolites derived from plants already in use in traditional medicine for treatment of skin and soft tissue diseases, including abnormal growths. The aims of our study are as follows:
Aim 1: Isolate individual potent and selective compounds from “hit” extracts. We will use classic bioassay-guided fractionation techniques to separate compounds found in our extracts of interest (all with initial IC50 < 8 µg/mL). Each of these is chemically complex, containing >100 major compounds each. HTS robotic platforms will be employed to screen refined fractions and then individual compounds for anti-cancer activity using established cell viability and NF-kB translocation assays with the A375 melanoma cell line. Selectivity and toxicity will be assessed with cell viability assays using a panel of 15 lung cancer cell lines and human keratinocytes (HaCaTs). We will use orthogonal separation approaches with different column chemistries to isolate individual compounds to be followed with dereplication strategies to identify any known molecules by LC-MS/MS and database analysis.
Aim 2: Determine the structure of isolated bioactive compounds. We will focus our structure elucidation efforts on those compounds demonstrating the most potent and selective activity, with priority given to compounds with good therapeutic indices of activity:toxicity (>100 fold difference) and to those compounds that appear to be novel in nature (not matching with any chemical databases).
Summary and Future Directions. Prior work indicates that the QNPL is a source of novel chemical entities (NCEs) with pharmacologically relevant activities. Here, we will identify compounds found in extracts from the QNPL to selectively target melanoma. This will represent the next step towards the identification of natural product scaffolds for future development in anti-cancer therapeutic development.