From Ideas to Impact
Pelotonia’s impact is perhaps most obvious in discoveries made and published in scientific journals by teams of researchers who have received Pelotonia support over the past few years. Some examples:
CanDL Database Shines Light on Clinically Important Cancer Gene Mutations
Many clinical trials use genome sequencing to learn which gene mutations are present in a patient’s tumor cells. The question is important because targeting the right mutations with the right drugs can stop cancer in its tracks.
But it can be difficult to determine whether there is evidence in the medical literature that particular mutations might drive cancer growth and could be targeted by therapy, or evidence showing which mutations are of no consequence.
To help molecular pathologists, laboratory directors, bioinformaticians and oncologists identify key mutations that drive tumor growth in tissues obtained during clinical studies, OSUCCC – James researchers, with support from Pelotonia and other funds, have designed an online database called the Cancer Driver Log, or CanDL.
The freely accessible database, described in a paper published in the Journal of Molecular Diagnostics, includes mutations in 60 genes, with 334 distinct variants and 169 unique matching literature references across multiple cancers as of October 2015.
“Currently, pathology laboratories that sequence tumor tissue must manually research the scientific literature for individual mutations to determine whether they are considered a driver or a passenger to facilitate clinical interpretation,” says principal investigator Sameek Roychowdhury, MD, PhD.
“CanDL expedites this time-consuming process by placing key information about known and possible driver mutations that might be effective targets for drug development at their fingertips. “CanDL does not tell doctors what to do—it places the evidence in the scientific literature at their fingertips, enabling them to read and interpret the information themselves,” he adds.
Identifying driver mutations in a patient’s tumor cells can also help reveal why some patients in a clinical trial respond well to a novel agent while others do not respond. That information can help improve the effectiveness of existing anticancer drugs and identify patients who would benefit most from particular therapies.
Prostate Cancer Androgen Receptor Activates Different Genes When Bound to Antihormone Drugs
A 2011 Pelotonia Idea Grant helped OSUCCC – James researchers led by Qianben Wang, PhD, conduct research that produced a surprising finding about a key receptor for testosterone, a hormone that drives prostate cancer development and progression.
That key molecule in prostate cancer is called the androgen receptor (AR). When testosterone activates that receptor, it causes the receptor to activate a certain set of genes. However, a study published in 2015 in The EMBO Journal by Wang and his colleagues showed for the first time that when the receptor binds with certain drugs (bicalutamide and enzalutamide) used to treat prostate cancer, it activates a completely different set of genes, including some that promote cancer.
The researchers called these newly discovered AR binding sites on DNA “antiandrogen response elements” and showed that they activate genes that might enable tumor progression during antiandrogen treatment.
Their findings suggest that the treatment of prostate cancer with antiandrogenic drugs should include agents that target antiandrogen-regulated oncogenes.
“The discovery of antiandrogen response elements was completely unexpected,” says Wang, noting that antiandrogen agents are known to work by competing with androgens to bind to AR, thus inhibiting androgen-induced gene expression.
“But we found that antiandrogens can also trigger AR to bind to DNA sequences that are distinctly different from androgen response elements, and thus regulate genes relevant to prostate cancer development,” says Wang, a member of the Molecular Carcinogenesis and Chemo-prevention Program at the OSUCCC – James.
Chitosan-Coated, ChemotherapyPacked Nanoparticles May Target Cancer Stem Cells
Funds from a postdoctoral fellowship helped support a study led by OSUCCC – James researchers that indicated nanoparticles packed with a chemotherapy drug and coated with an oligosaccharide derived from the carapace of crustaceans might target and kill cancer stem-like cells.
Cancer stem-like cells have characteristics of stem cells and are present in very low numbers in tumors. Highly resistant to chemotherapy and radiation, they are believed to play an important role in tumor recurrence. This laboratory-and-animal study showed that nanoparticles coated with an oligosaccharide called chitosan, and encapsulating the chemotherapy drug doxorubicin, can target and kill cancer stem-like cells six times more effectively than free doxorubicin. The study appeared in the journal ACS Nano.
“Our findings indicate that this nanoparticle delivery system increases the cytotoxicity of doxorubicin with no evidence of toxic side effects in our animal model,” says principal investigator Xiaoming (Shawn) He, PhD, a member of the OSUCCC – James Translational Therapeutics Program. “We believe chitosan-decorated nanoparticles could also encapsulate other types of chemotherapy and be used to treat many types of cancer.”
This study showed that chitosan binds with a receptor on cancer stem-like cells called CD44, enabling the nanoparticles to target the malignant stem-like cells in a tumor.
The nanoparticles were engineered to shrink, break open and release the anticancer drug under the acidic conditions of the tumor microenvironment and in tumor-cell endosomes and lysosomes, which cells use to digest nutrients acquired from their microenvironment.
He and his colleagues conducted the study using models called 3D mammary tumor spheroids (i.e., mammospheres) and an animal model of human breast cancer.