November 11, 2025
Compelling Stories from a Systematic Exploration of CTSC-Funded Pilot Projects
Since its inception in 2007, the Weill Cornell Clinical and Translational Science Center (CTSC) has provided seed funding to over 300 research teams. These competitive pilot awards provide protected time for researchers to pursue their original research ideas, helping advance the careers of many investigators. However, things don’t always go as planned. Sometimes, initial assumptions that ground the research plan turn out to be inaccurate or incomplete. The team is forced to pivot mid-course.
We began by compiling proposals and project reports for all successfully funded pilot awards at our CTSC. Proposals describe the planned research, and project reports detail activities and results at various check-in points. We prompted a 90-billion parameter version of Llama 3.2, a large language model (LLM), to identify projects in which the researchers encountered a barrier that required them to change their research direction, resulting in a discovery that was unanticipated at the project outset. Among the 311 sets of project documents, 35 projects were identified by the LLM as potentially fitting this general pattern. A manual review confirmed that 18 of these 35 clearly and definitively qualified. Four of the most compelling stories are highlighted here.
In 2010, principal investigator (PI) Ethel Cesarman, co-PI David Erickson, and co-investigator Susan Krown sought to develop an inexpensive method to detect Kaposi’s sarcoma herpesvirus (KSHV) in poor-resource settings. They initially sought to develop a microfluidics-based nanoparticle aggregation assay for the colorimetric detection of KSHV. However, they determined that the method lacked the sensitivity required for detection of the pathogen on its own – it would only work with polymerase chain reaction (PCR) amplification. In response to this challenge, the team developed an innovative solar-powered PCR technology – requiring only a cell phone and a lens – that could be used in poor resource settings. After developing a successful prototype, the team went on to publish several manuscripts on the discovery, later securing multiple large federal grants, including R01 and R21 awards, to apply their innovative approach and fund later related work. They’ve also received a UH2/UH3 award, and continue to improve and adapt the technology to speed up and reduce complexity in the processing of specimens.
The following year, PI David Mootoo and co-PI Nai-Kong Cheung successfully applied for a CTSC pilot project with the goal of creating antibody-drug conjugates (ADCs) using tetrahydrofuran-containing annonaceous acetogenins (THF-AGEs). The guiding hypotheses were that “a THF-AGE derived from an antibody that is specific to a cell surface antigen will be selectively delivered to cells that express the antigen as opposed to cells that do not express the antigen”, and that “after endocytosis, ADC processing releases a metabolite with potent cytotoxicity.” However, encountering synthetic difficulties with the THF-AGEs, they subsequently began examining sugar analogues of THF-AGE. They determined that the THF ring could be replaced with a simple carbohydrate residue without abrogating antitumor activity. This led to the discovery of a new analog of the THF-containing acetogenins, which retained potency but could be synthesized in much fewer steps. In follow-up studies, a pro-drug derivative of this lead molecule with potential selectivity for prostate cancer was synthesized. This new analog was designed to target prostate specific membrane antigen (PSMA), a clinically validated marker for PC. As proof of principle, cell assays on this prodrug revealed a 12-fold selective toxicity on PSMA positive compared to PSMA negative cells. This finding has provided insight for a new class of therapeutics against prostate cancer.
In 2013, PI Lonny Levin and co-PIs Jochen Buck, Fraser Glickman, and Nathan Radcliffe set out to screen FDA-approved drugs to identify potential modulators of soluble adenylyl cyclase (sAC), which plays a role in the pathogenesis of ocular hypotony and glaucoma. While initially confident, when they completed the screening, they had not identified any candidate drugs. They decided to expand their search to screen “a high diversity library of small molecules to identify new chemical entities which modulate sAC.” This led them to identify “a new sAC inhibitor called LRE1”, which led to a paper in Nature Chemical Biology, as well as substantial grants to support research towards developing an LRE1-based drug. The original hit was improved as a project of the Sanders Tri-I Therapeutics Discovery Institute, and the improved inhibitor revealed that a single dose of a sAC inhibitor can provide on-demand contraception in males. This work led to several grants from the National Institute of Child Health and Development, as well as several manuscripts, including a proof-of-concept paper published in Nature Communications in 2023.
Fast-forward to 2017. PI Dixie Goss, from Hunter College, joined co-PI Gregory Petsko on a CTSC pilot project with two main goals – first, to obtain the crystal structure of the protein eIF4G bound to an RNA oligonucleotide; and second, to examine eIF4G binding to other RNA structural motifs important in mRNA translation regulation. The first goal of obtaining the crystal structure was described as a “high risk, high impact project”. However, the progress reports indicate that the team ran into difficulties – despite trying a variety of experimental conditions, they were unable to obtain high quality crystals. However, they reported that they were able to create a “much more stable, biologically active form of the eIF4G protein”, which would allow them to pursue their binding studies. They wrote, “We were unable to obtain x-ray structures as we had originally hoped. However, by creating more stable proteins we were able to investigate binding to a set of mRNA that are expressed under stress conditions such as hypoxia which occurs in tumor cells.” This work led to an R01 grant application, which was successfully funded in 2019, and multiple publications in high-impact journals.The experiences of these researchers highlight the fact that CTSC-supported pilot projects play an important role in providing protected time for high-risk, high-reward research initiatives. Scientific research is complex and often nonlinear, with researchers sometimes forced to readjust and pursue new avenues. However, necessity is the mother of invention, and occasionally these new avenues lead to an important – and unexpected – discovery.
Michael Bales, MPH, PhD is the Director of Evaluation and Performance Management at the Weill Cornell Medicine Clinical and Translational Science Center