Engineering the Mechanics of Cancer Therapeutics

Mauro Ferrari, Ph.D.
President and CEO 
BrYet Pharma US, Inc.
 

Abstract

Genetic instability, a defining characteristic of cancer, increases dramatically with the progression of the disease, especially in its metastatic expressions. Therein, the mutational profile evolves, often quite rapidly. Molecular targets – the foundation of contemporary precision cancer biotherapeutics approaches – consequently further mutate and often disappear, thus disabling the mechanisms of action underlying therapies based on molecular recognition, such as monoclonal antibodies, kinase inhibitors, and antibody-drug conjugates. Thus, despite the momentous therapeutic advances brought by these medicines in several areas of oncology, and beyond, their effectiveness against metastatic cancer remains limited by the emergence of “therapeutic resistance”, largely eliminating any realistic hope for their curative intent, with therapeutic objectives remaining in the domain of extending median patient survival by a few weeks. Since cancer remains the primary cause of premature mortality in the world, the development of synergistic, next generation, or even alternative approaches to molecularly targeted therapeutic is thus a target that cannot be excluded a priori.

Upstream of molecular recognition, the notion of targeting cancer phenotypes may be one such approach that may yield therapeutic breakthroughs. Since phenotypes are comprised of a large number of individual molecular effectors and signaling mechanisms, they may be avenue leading to the development of therapeutic strategies that remain effective even as the molecular mutational profile of advanced cancers incessantly evolve.

In close collaboration with many extraordinarily talented investigators from a broad spectrum of vastly different scientific backgrounds, I have spent the last thirty years of my professional life on this quest. The primary focus has been on cancers of the lungs and liver (both primary and metastatic from any other organ in the body), since they cause the dominant majority of oncological mortality.

Based on the principles and methods of engineering mechanics, we formulated and validated a mathematical framework for the molecular transport phenotype of lung and liver cancers. Since these organs serve a primary function of molecular transport in the body, it is natural that their cancer counterpart is essentially a “hijacked” version of their function in health. It derives its key properties (“phenotypical nodes”) from the underlying physiology, largely irrespective of the cancer-associated molecular mutations. A cancer without these transport characteristics cannot proliferate uncontrollably, nor can it further metastasize. Thus, it is no longer a cancer.

In conjunction with a broad range of experiments both in laboratories and on preclinical models of cancer, over the years, this mathematical framework (“Transport Oncophysics”) served to identify the key phenotypical nodes of molecular mass transport in cancers of the lungs and liver. These nodes span a dimensional range of multiple orders of magnitude, from the centimeter level (microvascular site recognition, vascular trans-endothelial transport) to the millimeter (microenvironmental migration) to the nanometer (cellular membrane uptake, intracellular traffic, endosomal escape, and nuclear penetration). Concurrently, and again guided by the mathematical findings, we developed multi-component (“composite”) therapeutic agents that can act in a prescribed time sequence on all of these nodes – since just targeting an incomplete set of them does not yield the desired therapeutic efficacy.

ML-016, the lead composite drug we mathematically designed with this engineering mechanics methodology, comprises pDox, a new chemical entity further comprising a single amino acid peptide, poly (L-glutamic acid) or PGA, covalently conjugated to a conventional anthracycline chemotherapeutic agent, doxorubicin, via a pH-sensitive hydrazone linker. This peptide-drug conjugate is formulated with a mixture of conventional formulants, and a mesoporous silicon micron-sized element (“Si-plateloid”). The respective roles in the molecular transport phenotype targeting are that the Si-plateloid targets the cancer microvasculature based on physical principles (differential margination velocity caused by asymmetry of the element design), while the amino acid facilitates transport across the cancer vascular endothelium and throughout the dense tumor stroma. Driven by thermodynamics, pDox self-assembles in the tumor microenvironment to form exosome-mimicking vesicles, which are preferentially up-taken by the target, otherwise therapy resistant cells. Intracellular trafficking of the pDox vesicles conveys them actively to perinuclearly located late-stage endosomes and lysosomes, where the doxorubicin is released, to escape the endosomes and penetrate in high concentration in the cell nucleus, avoiding the multi-drug resistance ionic and molecular pumps that are largely located on the cell membrane of these cancer cell populations.

By way of this multi-step mechanism of transport, sequentially targeting the key nodes of the molecular transport phenotype of cancer of the lungs and liver, ML-016 was demonstrated to reproducibly yield complete cure rates of 60-80% in multiple preclinical models of metastatic cancer to the lungs and liver. These unprecedented efficacy findings, together with suitable results of regulatory-level safety and toxicity studies, and the development of clinical-grade manufacturing protocols formed the basis for our application for the beginning of clinical studies of Phase I/II in patients with any type of malignancy of the lung and liver, both primary and metastatic from any organ. The authorization to start these clinical trials was granted by the regulatory agencies of Australia in September, 2025.

In this presentation, I will review key steps of our 30-year journey from mathematical modeling of cancer to the clinical use of ML-016 and will present our most recent data. The fundamental role of engineering mechanics as guidance in this journey will be highlighted.

For further reading: 

https://pubmed.ncbi.nlm.nih.gov/26974511/ 
https://www.science.org/doi/full/10.1126/sciadv.aba4498

Biography

Mauro Ferrari’s first tenured faculty position was in Civil Engineering, at the University of California in Berkeley, where he served in the Division of Structural Engineering, Mechanics and Materials. In this capacity he first joined ASCE in 1993 and received a Presidential Young Investigator Award from the NSF, which laid the foundations for his work in cancer therapeutics, for the rest of his professional career. His laboratory there was the birthplace of nanomedicine, bioMEMS, nanofluidics, silicon microparticles as a cancer therapeutic agent, and silicon-encapsulated immunoisolated cell transplants. 

His education encompassed a degree in Mathematics from the University of Padova, both MS and PhD degrees in Mechanical Engineering from UC Berkeley (with a minor in Civil Engineering). He studied Medicine at The Ohio State University, and received his executive education from Harvard Business School and the Wharton Business School of the University of Pennsylvania. 

Following Berkeley, his academic career included endowed full professor positions in both engineering and medicine, at: The Ohio State University (also, Director of Biomedical Engineering and University Associate Vice President); The University of Texas Medical School and MD Anderson Cancer Center in Houston (also, Chairman of Nanomedicine and Biomedical Engineering); The Houston Methodist Hospital (also, President and CEO of the Research Institute for 10 years, and Executive Vice President of the Houston Methodist Hospital System). He also served as Eminent Scholar and Special Advisor to the Director at the National Cancer Institute of the USA, and President of the European Research Council (ERC). He currently serves as Affiliate Professor (Entrepreneur-in-Residence) of Pharmaceutics at the University of Washington in Seattle WA.

As an academic investigator, he has published over 500 archival articles, 7 books, has secured about one-hundred patents, and was awarded many recognitions including honorary degrees from the University of Naples “Federico II” (biotechnology) , the University of Palermo (electrical engineering) and election to the Italian National Academy of Sciences “Detta Dei Quaranta” as a foreign member.

A life-long scientist entrepreneur, since 2020 he has prioritized his engagement in the pharmaceutical industry. He currently serves as President and CEO of BrYet Pharmaceutics in Houston TX. He has been serving as a member of the Board of Directors of Arrowhead Pharmaceuticals (NASDAQ:ARWR) since 2010, chairing its scientific governance since its inception. Through his work at BrYet and Arrowhead, he brought twenty-three innovative medicines from research laboratories into clinical use. In his leadership position at the Houston Methodist Hospital, he supervised over one thousand clinical trials and protocols, in multiple domains of medicine.

He credits his accomplishments in medicine to the scientific mind-frame and knowledge base he derived from his education and work in engineering mechanics.