The first de novo prepared nanoparticle drug, designed to overcome standard cancer drug resistance, is helping patients with four different cancers.
That report was made at this week’s International Conference on Molecular Targets and Cancer Therapeutics in Boston, Mass.
“The good news is that our findings in animals translate to humans,” says California Institute of Technology chemical engineer Mark Davis. Davis began as a chemical engineer in the oil industry, not oncology. But after his wife contracted breast cancer, he switched careers at age 40 to engineer a drug that would be less toxic and more effective than the ones she was prescribed.
The initial result of his efforts is a drug called CRLX101. It was created from scratch to aid anti-angiogenic drugs, which cut off blood supply to a tumor. Via the expression of a protein called HIF-1 alpha, tumors develop resistance to anti-angiogenic drugs. HIF-1 alpha spurs tumor metastasis and the proliferation of virulent tumor stem cells.
Anti-angiogenesis, the brainchild of Harvard University researcher Judah Folkman, was once predicted to be a cancer cure by molecular biologist Jim Watson who discovered the structure of DNA. But at least in part because of HIF-1 alpha, it has not lived up to its billing.
Intent on changing this, Cerulean Pharma Inc., which licensed Davis’s drug, has been trying CRLX101 on patients with four different cancers, in four different Phase 2 clinical trials.
When given to nine kidney cancer patients, CRLX101, alongside the anti-angiogenic drug bevacizumab, prompted a 33 percent partial response rate. This is “unprecedented,” according to Cerulean. For the overall response rate is normally four percent with bevacizumab alone, and only two percent with everolimus, the standard of care.
The maximum tolerated dose of CRLX101, in combination with bevacizumab, was the same as bevacizumab alone, suggesting the combo had relatively low toxicity.
Imaging of patients in a gastric cancer clinical trial found more accumulation of CRLX101 in tumors than in neighboring healthy tissue. This indicated the nanoparticle may be target-specific.
Also ongoing are two clinical trials to test CRLX101 alone in patients with small-cell lung cancer and ovarian cancer. By 2014, two additional combination trials will be launched. One will offer CRLX101 with bevacizumab to ovarian cancer patients. The second will combine it with capecitabine and radiation to rectal cancer patients.
The company reported that, in animals, the drug has shown synergy when added to every anti-angiogenic agent tested.
“There are many reasons why we believe CRLX101 functions as it does,” says Davis, who has given a TED talk and a Public Broadcasting Service (PBS) interview on his novel nano work. “The entire nanoparticle system was designed with certain properties like size (small, so it has good tumor penetration and can center cells). It is also slightly negatively charged to provide long circulation time and very low side effects.”
The drug ferried into tumors by the nanocarrier is camptothecin. It is normally highly toxic to patients. But when broken into nanoparticles of 20 to 30 nanometers in diameter that are join by polymeric materials, it is preferentially taken up by tumor cells, sparing other tissues and making it less toxic, suggest animal data.
Published last month in the August issue of the Proceedings of the National Academy of Sciences, that data indicate that chemical linkers in the nanoparticle release the payload slowly, which guarantees a slow and sustained release of camptothecin. This enables durable inhibition of an enzyme called topoisomerase-1, which in turn leads to inhibition of HIF-1 alpha.
“The coupling chemistry between the drug and the polymer by design gives slow release of the drug once the nanoparticle is inside the cancer cell, as the biology tells one that this is the best way to kill cancer cells,” explains Davis. “So this nanoparticle is a small chemical system for which each of the multifunctional properties were built into it by design.”
Davis says the success of his approach may derive in part from the fact that he came at the problem as an engineer who looks for new ways to build things, not a classically trained oncologist who analyzes existing molecules for potential efficacy. "I treated the problem as an engineering problem," he says. "The nanoparticle had to do the right things in the right places at the right times: the multifunctions."
He adds that he has since gone on to create a second nanoparticle "which we have taken to clinical trial, and has utilized new biology (RNA interference)."
The 2013 International Conference on Molecular Targets and Cancer Therapeutics is co-hosted by the American Association for Cancer Research, the National Cancer Institute, and the European Organization for Research and Treatment of Cancer.