New Nanopharmaceutical May Be Able to Overcome Resistance to Antiangiogenic Treatment

Key Points

  • The nanopharmaceutical CRLX101 is a novel inhibitor of topoisomerase-1 and HIF-1 alpha, and as such may be able to overcome resistance mechanisms associated with antiangiogenic treatment.
  • Preclinical studies in renal cell carcinoma and ovarian cancer show that CRLX101, when given in combination with bevacizumab and other antiangiogenic agents, produces robust tumor inhibition and prolongs survival.
  • Early clinical studies suggest high response rates in refractory renal cell carcinoma patients.

The nanopharmaceutical CRLX101, a novel inhibitor of topoisomerase-1 and hypoxia-inducible factor (HIF)-1 alpha, may be capable of overcoming resistance of tumors to antiangiogenic agents, according to preclinical and early clinical studies that have evaluated CRLX101 in combination with bevacizumab (Avastin) and other antiangiogenic agents.

Scott Eliasof, PhD, Vice President of Cerulean Pharma Inc, Cambridge, Massachusetts, presented preliminary results at the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, held October 19 to 23 in Boston (Abstract PR09/B1). At a press briefing, Dr. Eliasof said early results are “particularly exciting” because, until now, HIF-1 alpha was considered “undruggable.”

Tumors treated with antiangiogenic agents usually develop resistance to these drugs, often because of the upregulation of HIF-1 alpha, a protein that promotes tumor invasion, metastasis, and cancer stem cell formation. “Until now, HIF-1 alpha has been considered impossible to target safely, but CRLX101 may change that,” he predicted.

Synergy is observed when CRLX101 is combined with an antiangiogenic agent or radiation, with limited toxicity, making it safe to combine with other agents, Dr. Eliasof said. “We see very few high-grade adverse events. This is markedly in contrast to published data with irinotecan and topotecan, the other HIF-1 alpha inhibitors, which carry a high degree of hematologic and gastrointestinal toxicity,” he pointed out.

Drug Details

CRLX101’s payload is camptothecin, a topoisomerase-1 inhibitor that has not been clinically useful on its own, chemically conjugated into nanoparticles of 20 to 30 nm in diameter. When CRLX101 is taken up by tumor cells, the chemical linkers release camptothecin slowly. The sustained release enables durable inhibition of topoisomerase-1, which in turns inhibits HIF-1 alpha.

“CRLX101 inhibits topoisomerase-1, but what is so unusual and exciting is that it also inhibits HIF-1 alpha, a major player in cancer cell survival,” Dr. Eliasof emphasized. “We think HIF-1 alpha inhibition is important because it plays a role in angiogenesis, drug resistance, metastasis, and cancer stem cells. Antiangiogenesis drugs and radiation cut off blood supply, which will increase hypoxia. Hypoxia drives HIF-1 alpha up and turns on the cancer survival pathways. When we combine CRLX101 with an antiangiogenic agent or radiation we might overcome this mechanism of resistance.”

Single doses of the drug, equivalent to human dose levels, were shown to inhibit HIF-1 alpha by 70% or more. In a colorectal cancer model, a single dose produced 95% inhibition lasting more than one week. “This durability is quite important for HIF-1 alpha because it is an important transcription factor. This isn’t possible with irinotecan or topotecan, the existing topoisomerase-1 inhibitors,” Dr. Eliasof pointed out.

The synergistic effect of the combination, vs single agents, has been shown in multiple tumor models and with a variety of antiangiogenic agents, including bevacizumab, pazopanib (Votrient), and ziv-aflibercept (Zaltrap), which have a modest effect on tumor growth as monotherapy. Single-agent CRLX101 at therapeutically relevant doses produces some tumor inhibition and improvement in survival, but the combination of the agents is synergistic and robust. Similar synergy is seen when CRLX101 is combined with radiation, he said.

“These findings suggest we can overcome the resistance mechanism that is caused by the increase in HIF-1 alpha,” he reiterated.

“Another interesting consequence of inhibiting HIF-1 alpha relates to the role that it may play in stem cells,” he added. In a mouse model of triple-negative breast cancer, researchers extracted 100 cells from each animal and implanted them in a second mouse. The appearance of new tumors, a measure of stem cell activity, was essentially not inhibited at all by bevacizumab, was somewhat inhibited by CRLX101 monotherapy, but was largely prevented by CRLX101 plus bevacizumab, which indicated that cancer cell upregulation was prevented.

Early Clinical Trial Data

Based on this encouraging preclinical work, the company has initiated several phase II investigator-sponsored clinical trials testing CRLX101 as a single agent or in combination with an antiangiogenic agent.

The investigators hope to demonstrate proof of concept in a phase Ib/IIa renal cell carcinoma trial that is evaluating CRLX101 with bevacizumab. Renal cell carcinoma patients have a deleterious mutation in the von Hippel-Lindau gene that creates high levels of HIF-1 alpha. “We think this is a great opportunity to show what HIF-1 alpha inhibition can do,” Dr. Eliasof said.

Of nine patients treated, three (30%) had a response by RECIST criteria. Considering that the response rate to bevacizumab alone is typically just 4%, “this is a really dramatic finding,” he said at the press briefing. “This is only in nine patients, but it’s very promising.” Patients’ disease remained stable for much longer than had been achieved with previous regimens, he added.

Cerulean will also evaluate CRLX101 in relapsed ovarian cancer, small cell lung cancer, and in rectal cancer in the neoadjuvant setting, in combination with capecitabine and radiotherapy.

Previous studies in non–small cell lung cancer were not as encouraging, Dr. Eliasof acknowledged, with response rates of about 10%. “The results were not markedly better than currently approved treatments in the second and third line, so we decided not to pursue the drug [in lung cancer],” he said in response to a question at the press briefing.

Dr. Eliasof is an employee of Celulean Pharma Inc, which funded this study.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.




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