How MSKCC's Screening Platform is Revolutionizing Drug Discovery
Imagine hundreds of thousands of tiny experiments running simultaneously, each holding a promise to yield potential leads in the fight against cancer.
This isn't science fiction—it's the daily reality at Memorial Sloan Kettering Cancer Center's (MSKCC) cutting-edge screening facilities, where scientists harness advanced robotics and sophisticated data analysis to rapidly test chemical compounds and genetic treatments against devastating diseases 1 . In facilities that look more like something from a futuristic movie than a traditional laboratory, researchers are conducting a microscopic hunt for new cancer therapies, repurposing existing drugs for new applications, and making discoveries that could pave the way for better treatments for patients worldwide 1 2 .
This article explores how MSKCC's collaborative platform combines chemical screening and RNA interference (RNAi) technologies to accelerate drug discovery. We'll delve into the science behind these approaches, examine a groundbreaking discovery that emerged from this work, and consider how these tiny experiments are making a massive impact in the fight against disease.
MSKCC's High-Throughput Screening Core Facility (HTSCF) represents a significant commitment to innovative cancer research. Established in 2003 and later expanded in 2006, this state-of-the-art facility occupies specialized laboratory space designed specifically for large-scale screening operations 1 .
The power of HTSCF lies in its extensive collection of research materials. The facility maintains a diverse chemical library of approximately 400,000 compounds sourced from established vendors worldwide 1 .
Chemical Compounds
Human Genome Coverage
Facility Established
Service Support
To understand the significance of MSKCC's work, it helps to understand RNA interference (RNAi). This natural cellular process uses small snippets of RNA—just 21 or 22 nucleotides long—to bind to specific messenger RNAs (mRNAs) and repress them 2 .
Think of mRNA as a recipe book that tells cells how to make proteins; RNAi works by effectively bookmarked with a "do not read" tag on specific recipes, preventing certain proteins from being produced.
This process has been harnessed by scientists to create therapies that can silence disease-causing genes. The first siRNA drug, patisiran, was approved by the FDA in 2018 to treat a debilitating genetic disorder called hereditary transthyretin amyloidosis 2 .
Small interfering RNA (siRNA) is introduced into the cell
siRNA is loaded into the RNA-induced silencing complex (RISC)
RISC identifies complementary mRNA sequences
mRNA is cleaved and degraded, preventing protein production
Designed using the SplashRNA algorithm with >90% of high-scoring predictions triggering >85% protein knockdown 7
shRNA & sgRNA pooled libraries for large-scale genetic screens 7
Systems that use catalytically inactive Cas9 to either repress or activate gene expression 7
"But instead, we were surprised to see them increase," Dr. Lai recalls 2 .
Some of the most important scientific discoveries happen completely by accident. That's exactly what occurred when a team of MSKCC researchers led by developmental biologist Eric Lai, PhD, and postdoctoral fellow Seungjae Lee, PhD, made an unexpected finding while studying a protein called ALAS1 2 .
The researchers were testing how ALAS1 helps to make microRNAs. When they removed the protein from cells, they expected to see microRNA levels drop. "But instead, we were surprised to see them increase," Dr. Lai recalls 2 . This counterintuitive result led to the discovery of an unrecognized role for ALAS1 beyond its well-known function in heme production.
Removed ALAS1 and observed increased microRNA levels
Tested other enzymes in heme biosynthesis pathway
Partnered with Mount Sinai experts
Confirmed findings in animal models
This discovery revealed that ALAS1 acts as a brake on microRNA production. Understanding this mechanism provides an opportunity to improve siRNA therapies. "So we thought, now that we know how to remove this brake, maybe we can use that to improve the efficacy of siRNA drugs and their ability to silence their target genes," Dr. Lai explains 2 .
Coincidentally, one of the six approved siRNA drugs (givosiran) already turns off ALAS1 to treat acute hepatic porphyrias. This raises the possibility of combining such an agent to enhance other siRNA drugs—a strategy that could be generally applicable to any siRNA therapeutic 2 .
While discovering new drugs is valuable, MSKCC's screening platform has also demonstrated success in repurposing existing FDA-approved drugs for new applications. In one notable case, the anti-arrhythmia drug digoxin was identified through primary HTS and subsequently administered in the clinic for treatment of stage Vb retinoblastoma, a type of eye cancer 1 .
This approach to drug repurposing offers significant advantages. Since safety profiles for already-approved drugs are well-established, repurposed treatments can potentially reach patients more quickly than completely novel compounds. The HTSCF's extensive library includes numerous FDA-approved compounds specifically to facilitate this type of discovery 1 .
Reduced development time compared to new drugs
Lower development costs
Established safety data from previous use
| Library Source | Type of Compounds | Number of Compounds |
|---|---|---|
| Prestwick Chemical | FDA-approved & known bioactives | 1,280 |
| MicroSource Spectrum | FDA-approved & known bioactives | 2,560 |
| Selleck Chemicals | FDA-approved & known bioactives | 1,280 |
| MedChemExpress | FDA-approved Drug Library | 2,377 |
| LOPAC | Pharmacologically active compounds | 1,280 |
The screening facilities at MSKCC don't operate in isolation—they're part of a larger collaborative ecosystem designed to foster innovation. The institution's collaborative research centers draw on the breadth of scientific expertise, bringing together laboratory investigators and clinicians from different disciplines to focus on strategically important areas of cancer science 4 .
This integrated approach extends to management structures specifically designed to support core facilities. The Office of Core Facility Operations provides oversight to ensure optimal services that support the Center's research mission, reviewing infrastructure needs including space, equipment, staffing levels, and monitoring budget and cost effectiveness 1 .
| Reagent Type | Specific Examples |
|---|---|
| Chemical Libraries | Selleck Bioactive Library, LOPAC, Prestwick FDA Library |
| RNAi Libraries | Silencer Select V4.0 Library, custom shRNA collections |
| Vectors | miR-E vectors, CRISPR-Cas9 systems, overexpression vectors |
| Cell Lines | Cancer cell lines, PDX models |
| Screening Platforms | IN Cell Analyzer 6000, IncuCyte S3 |
Information sourced from MSKCC core facility descriptions 1 6 7
"In academia, it is more gratifying because you can see compounds move into the clinic. In industry, the more the compound progresses, the less you hear about it." - Dr. Djaballah, former director of the HTS Core Facility 9
The field of high-throughput screening continues to evolve at a rapid pace. MSKCC has consistently expanded its capabilities, adding high-content screening (HCS) in 2010, which combines automated microscopy with sophisticated image analysis 1 . The facility now houses some of the most advanced instrumentation available, including the only fully automated alpha INCA3000 unit in the world at the time of its installation 1 .
More recently, MSKCC has joined the Cancer AI Alliance (CAIA), a research collaboration of top cancer centers that aims to accelerate discoveries using artificial intelligence . This alliance has launched the first scalable platform using federated learning for cancer research, enabling scientists to train AI models on diverse, multi-institutional clinical data while maintaining security and privacy .
Added in 2010, combines automated microscopy with image analysis 1
Including the fully automated alpha INCA3000 unit
Joining top cancer centers to accelerate AI-driven discoveries
Training AI models on multi-institutional data while maintaining privacy
Beyond the direct research applications, MSKCC's screening facilities serve an important educational function. The facility provides opportunities for students and postdoctoral research fellows to gain experience and training in HTS and drug discovery 1 . This training aspect helps ensure that the next generation of scientists will be equipped with the skills necessary to advance the field.
The work happening at MSKCC's screening facilities demonstrates how tiny experiments—testing individual compounds or silencing specific genes—can lead to major breakthroughs in our understanding and treatment of disease.
From unexpected discoveries like the dual role of ALAS1 to systematic repurposing of existing drugs, these approaches represent powerful weapons in the fight against cancer and other devastating illnesses.
"When people ask why we're not spending all of our research dollars directly studying diseases like cancer, why we're funding research into cells and processes in model organisms like fruit flies, yeast, and bacteria—this is a great example of how discovery science fuels the biggest breakthroughs." - Dr. Lai 2
The collaborative platform at MSKCC, combining chemical and RNAi screening with translational research expertise, continues to push the boundaries of what's possible in drug discovery. Each of those hundreds of thousands of tiny experiments running simultaneously in the high-throughput screening facility represents not just a potential lead compound, but hope for patients waiting for better treatments—proof that sometimes the smallest things can have the biggest impact.