Cancer Drug Development: Views from Industry
In the lecture, Dr. Engelman masterfully wove through the labyrinthine pathways of cancer drug development, shedding light on the intricacies and challenges of pioneering groundbreaking pharmaceutical solutions in oncology.
The principle of Target Validation is central to the entire architecture of drug discovery. This process is not just about pinpointing a cellular or molecular target but ensuring that this target is fundamentally necessary and sufficient to cancer cells’ malignant growth and survival. Such targets can vary in their origin; while some are genomic-dependent, emerging directly from the very DNA mutations that characterize certain cancers, like BCR-ABL, others, such as CD19, are lineage-dependent, tracing back to specific cellular lineages. Instruments like genome-wide CRISPR genes and the groundbreaking DEPMAP have irrevocably transformed our approach to functional genomics, opening up new horizons in targeted therapy research. PDX mouse models, invaluable for predicting treatments’ efficacy in humans, particularly shine when evaluating small molecule inhibitors. Yet, as is the nature of science, they have their limitations – notably, diminished applicability in the field of Antibody-Drug Conjugates(ADCs).
The delineation of a Clear Patient Population with unmet medical needs is the second keystone in this intricate edifice of drug development. The medical landscape is vast and varied, and within its expanse, there lie populations of patients whose therapeutic needs remain unsatisfied. It’s within these voids, these therapeutic deserts, that the most pressing challenges – and the greatest opportunities – lie. Identifying and addressing these niches ensures that the new wave of drug solutions doesn’t merely add to the existing repertoire but fills a previously unmet, pressing need.
Venturing further into the complex terrain, the Therapeutic Index emerges as the third and most important pivotal beacon. At its heart, this metric is a delicate dance between therapeutic promise and potential peril. Every clinical trial investigator needs to consider this concept thoroughly before proceeding with clinical trial testing, as it can cause significant harm to patients if not followed. Every drug, regardless of its efficacy, must be rigorously evaluated for toxicity. For instance, while pan-kinase inhibitors might showcase a promising offensive against cancer cells, their potential toxicity to healthy tissues cannot be overlooked. On the other hand, dispensable lineage can be used in drug discovery such as B cell lymphoma, prostate cancer, and breast cancer. One of the best examples is antiCD19 CAR-T. Anti-CD19 CAR-T effectively decimates an entire lineage of B cells, but patients are able to survive without B cells for a period of time until it recovers. Here, preclinical models, especially the invaluable mouse knockouts, including inducible knockouts, provide crucial insights, guiding researchers through the treacherous waters of drug safety and effectiveness.
The lecture’s crescendo is reached with the theme of Druggability. This domain is not just about the scientific challenge of targeting a molecule but the feasibility of doing so effectively. Certain targets, like MYC with flexible structures, stand as seemingly insurmountable challenges, defying numerous drug intervention attempts. Conversely, other entities, like specific kinases or catalytic enzymes, with their well-defined structures, appear more amenable. Beyond the molecular target lies the strategic arena of drug delivery. ADCs, designed for rapid cellular internalization, stand in contrast to bispecific drugs, which are tailor-made to operate outside the cellular environment.
To encapsulate, Dr. Engelman’s lecture was more than just a presentation; it was a panoramic voyage into the multifaceted world of cancer drug development. It captured the essence of innovation, the challenges of targeted research, and the unwavering commitment required to navigate the intricate nuances of drug design, delivery, and efficacy.