EPR Effect: Cancer’s Achilles Heel, or Red Herring?

“It’s been a rapid rise and fall,” says Eric Schmidt, a biotechnology analyst at the investment bank Cowen and Company in New York City. “It’s all unraveled pretty quickly.”Nature.Com, Bankruptcy Filling Worries Developers of Nanoparticle Drugs. 

Three decades ago, Rakesh Jain, a researcher working at the Carnegie Mellon University Department of Chemistry, published a series of papers describing the micro-environment inside solid tumors. The focus of one of Jain’s observations birthed the cancer nanotechnology industry. Ignoring another of Jain’s observations sent researchers and the cancer nanotechnology industry down a rabbit hole resulting in countless years of wasted effort and hundreds of millions of dollars of misspent investment.

Jain’s review of his own work in 1987 described an imbalance of fluid flow into and out of solid tumors. Like Jain, pioneering Japanese researcher Hiroshi Maeda, observed and published numerous papers describing how blood vessels growing inside solid tumors, regardless of tumor type and origin, have small gaps (~120-1200nm), which along with other tumor blood vessel abnormalities, allow fluid and blood components (but not blood cells) to pour into the tumor micro-environment. These leaky blood vessels combined with research demonstrating that tumor lymphatic vessels do not properly drain fluid from tumors led to two of the most important findings in cancer research over the last thirty years:

  1. Large molecules, such as nanoparticles (roughly the size of a virus), which do not escape blood vessels in healthy tissues, pass through gaps in solid tumor blood vessels and concentrate “inside” the tumor.
  2. Leaky blood vessels create fluid build-up inside solid tumors resulting in high-pressure gradients that surround cancer cells in the tumor’s interior.

Hiroshima Maeda coined the term Enhanced Permeability and Retention (EPR) Effect to describe these phenomena. For more than a decade hundreds of researchers and several companies have invested time and significant capital designing nanomedicines to take advantage of the EPR effect to deliver therapeutics into solid tumors. However, these efforts ignored the second and arguably more important discovery — that high-pressure gradients inside tumors push nanomedicines to the periphery of the tumor, preventing them from reaching and killing cancer cells.

Overlooking this obvious defect, many flawed nanomedicine constructs attracted investment and media attention because they demonstrated the ability to move highly toxic anti-cancer agents through the patient’s blood stream with fewer side effects than existing delivery mechanisms. Moreover, most nanomedicines used pre-clinical mouse data, primarily in xenograft mice, to demonstrated high levels of therapeutic efficacy. Taken together, promising preclinical efficacy and lower toxicity led many to believe that nanomedicines, taking advantage of the EPR effect, would revolutionize cancer treatment. Yet, despite these early promising results, the cancer nanotechnology industry has repeatedly failed to demonstrated success in late phase clinical trials. Why? Cancer nanomedicine companies and products fail if they only address half of the EPR effect.

Nanoparticles do not penetrate deeply enough into solid tumors to be effective. Xenograft mouse models are especially unreliable predictors of clinical efficacy for nanotechnology constructs because they create disproportionately large tumors with blood vessels that enhance entry of nanoparticles while minimizing the high-pressure gradients that we know exists inside human solid tumors. Relatively speaking, if a human had a tumor comparable to that seen in mouse xenograft models, it would fill a wheelbarrow. The choice of poor preclinical animal models combined with the success of nanomedicine Phase I clinical trials showing fewer side effects and lower toxicity, strengthened investment in products that were doomed to fail.

Recent research has suggested that the EPR Effect alone only modestly improves the concentration of nanoparticles in solid tumors (~2x). Nature recently reported that, on average, only 0.7% of a nanomedicine’s delivered dose concentrates inside the tumor. Moreover, dynamic fluid tumor models indicate that the high-pressure gradient inside solid tumors more effectively pushes nanoparticles to the periphery of the tumor than the small molecule chemotherapies they were meant to replace. To put it plainly, nanoparticles stay inside the tumor longer than small molecule therapies and at slightly higher concentrations, but they are less effective at reaching cancer cells. These facts are likely behind the recent clinical failures of products from industry leading companies, BIND Therapeutics and Cerulean.

Research and clinical data have shown that when the fluid pressure inside the tumor is relieved, better clinical results can be obtained. Mouse models using genetically engineered mice, which naturally develop tumors, which are indistinguishable pathologically from human tumor tissue, have shown that reducing internal tumor fluid pressure causes a dramatic increase in the tumor concentrations of small and large molecule therapies. While there are multiple avenues to achieve reduced tumor pressure, the most effective and complete result can be achieved by using a vascular disruption agent (VDA). VDA’s cause the complete collapse of the blood vessels feeding solid tumors.

When Jain and Maeda began their work more than thirty years ago, VDA’s could not be delivered systemically because of their toxicity. However, VDAs can now be attached and delivered into tumors using nanoparticles. And unlike other chemotherapies, because VDAs act on blood vessels, the high-pressure gradient inside tumors, which pushes nanoparticles toward the tumor’s periphery may be beneficial to concentrating these agents where they can most effectively cut off the proverbial “spigot” driving the tumor’s internal high-pressure gradients. Once the fluid pressure inside the tumor drops, not only are nanoparticles able to penetrate more deeply into the tumor’s interior, but standard chemotherapies, biologics, immunotherapies and even cellular therapies gain significantly greater access to the cancer cells they were designed to kill.

It is clear — the EPR effect has been a Red Herring for those researchers and companies who have chosen to ignore the problem of internal tumor pressure. In the end, it is likely that cancer’s Achilles Heel lies in solving the internal pressure problem, which will be far more impactful for cancer patients than taking advantage of the EPR effect to facilitate nanoparticle entry into tumors, though the former cannot be done currently without the latter.

Still, in the face of mounting clinical evidence and repeated failure, many researchers and companies continue to pursue nanotechnology constructs that do not address the high-pressure gradient inside the tumor micro-environment. They do this to the peril of their investors, and to the detriment of their most important stakeholder, the cancer patients whose lives depend on the clinical success of these products.

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