Several Phase II studies of a novel nanoparticle agent indicate that combining it with a common antiangiogenic drug could provide a new way to treat patients with cancers who gradually develop resistance to antiangiogenic drugs and radiation therapy, according to data presented at this year's International Conference on Molecular Targets and Cancer Therapeutics, cosponsored by the American Association for Cancer Research, National Cancer Institute, and European Organization for Research and Treatment of Cancer.
Antiangiogenic drugs have become a mainstay of cancer treatment because they reduce blood flow to tumors and thereby inhibit tumor growth by starving tumors of oxygen and nutrients. However, they have limited success as monotherapies, in part because of their induction of hypoxia and upregulation of hypoxia-inducible factor 1α (HIF-1α), which promotes tumor angiogenesis, invasion, metastasis, and cancer stem cell formation.
Many traditionally treated patients in remission subsequently develop recurrence due to this. Scott Eliasof, PhD, Vice President of Research for Cerulean Pharma, Inc., in Cambridge, Mass., told attendees that a 33 percent partial response has been seen in a trial with nine kidney cancer patients who were treated with the drug CRLX101, combined with the antiangiogenesis agent bevacizumab.
The response rate is “unprecedented,” he said, because the response rate is usually only about four percent with bevacizumab alone, and two percent with everolimus, which is the standard of care for patients who develop resistance.
“Even though this data is only in nine patients, compared with these other treatments, I think 33 percent with CRLX101is hitting it out of the park.”
Two other clinical trials are also underway investigating CRLX101—one as monotherapy in small-cell lung cancer and the other as a combination agent in ovarian cancer. Cerulean is also launching additional combination trials, including one testing response with CRLX101 combined with capecitabine and radiation in neoadjuvant rectal cancer.
The researchers conducted an imaging trial in patients with gastric cancer, which showed that more CRLX101 accumulated in tumors than in healthy neighboring healthy tissue, suggesting that the compound has the potential to be target-specific, he said.
“To date over 200 patients are enrolled in different trials. We would have tested the combination in ovarian cancer but we wanted to first see how well it worked as a monotherapy,” Eliasof said in a telephone interview after the meeting.
He said that the study has shown that CRLX101 has few side effects, which may permit it to be effectively combined with other drugs.
CRLX101 inhibits hypoxia-inducible factor 1-alpha, or HIF-1alpha, a transcription factor found in high levels in malignant solid tumors, but not in normal tissues or slow-growing tumors. In fast-growing tumors, the drug is involved in activating a number of cellular processes, including resistance against apoptosis and angiogenesis, as well as metastasis.
The drug delivers camptothecin, a toxic anticancer drug that has been conjugated into nanoparticles using polymeric materials. Preclinical data, he noted, indicate that when taken up by tumor cells, camptothecin is released slowly and steadily, allowing the agent to be released over time, providing sustained inhibition of topoisomerase-1, an enzyme which leads to the inhibition of HIF-1 alpha.
“Until now, HIF-1alpha has been considered impossible to target safely, but CRLX101 may change that,” Eliasof said.
A single dose of CRLX101 inhibited HIF-1α protein levels across multiple tumor types, the researchers found, and evaluation of the drug combined with bevacizumab, aflibercept, or pazopanib in the A2780 ovarian xenograft tumor model all have shown tumor growth inhibition as well as increases in the rate of long-term survivorship.
“While all three antiangiogenic drugs alone increased HIF-1α protein levels, the levels were inhibited in response to combination with CRLX101,” Eliasof said. “It appears to be safe and well tolerated, with no dose-limiting toxicities observed to date, with tumor decreases and long periods of progression-free survival among treated patients, both as a monotherapy and in combination with the other agents tested.”
Asked for his opinion for this article, Bruce Zetter, PhD, the Charles Nowiszewski Professor of Cell Biology at Harvard Medical School and Chief Scientific Officer at Boston Children's Hospital Vascular Oncology Program, explained that nanoparticle cancer drugs offer several potential advantages over traditional therapies.
“The rationale behind nanopharmaceutical drug delivery is that they can direct more of a drug to a target tumor and less to the rest of the body, and this should reduce the whole body toxicity associated with standard chemotherapeutic drugs that were previously used at levels close to their maximally targeted dose,” he said.
Nanoparticle delivery systems may also increase the drug load to tumors and possibly increase drug efficacy, because they slowly release the drug over time, which provides an opportunity to use less frequent dosing.
“In practice, the effects of this general class of anticancer drugs to increase drug safety have been fairly dramatic,” Zeller said. “The effects on increasing drug efficacy have been significant, and are expected to get even better as we find the optimal ways to use these drugs and identify the tumors that respond best to each specific drug.”
He called CRLX101 “an iconic example of this class of drug, because it allows increased safety of a classic chemotherapeutic drug, camptothecin, whose use has been limited by high toxicity.”
Because of its safety profile, CRLX101 can be readily combined with other drugs. In one clinical trial, he said, it is being used in combination with the VEGF antagonist bevacizumab in the treatment of renal cell carcinoma, and clinical responses are being seen in this difficult-to-treat tumor. Another trial involves the use of CRLX101 in combination with capecitabine and radiation in colon cancer patients.
Two Separate Anti-Tumor Mechanisms
“Scientists at Cerulean have shown that CRLX101 has at least two separate anti-tumor mechanisms,” Zetter continued. “The first is to antagonize topoisomerase 1, the classic target of Irinotecan. The second is to antagonize Hif1 alpha, an important mediator of angiogenesis and multiple tumor survival mechanisms.”
Hif1alpha has not previously been targeted successfully by known anticancer drugs, and having activity on two separate tumor pathways allows CRLX101 to have greater antitumor efficacy than drugs that target only one or the other, he said.
“To me, CRLX101 represents the tip of the iceberg in showing the efficacy of this type of drug delivery. Other drugs are being prepared in the same platform and are moving rapidly toward clinical trial. An example is CRLX301, which improves the safety profile of docetaxel and provides improved antitumor activity in preclinical studies. Clinical trials of CRLX301 are expected to begin by the end of 2014.”