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Therakos Cellex: Mechanism of Action

Published Online:4:58 PM, Tue November 20, 2012
A randomized double-blind phase III trial comparing vintafolide plus pegylated liposomal doxorubicin (PLD) versus PLD plus placebo in patients with platinum-resistant ovarian cancer (PROCEED).

The primary objective is to assess PFS based on investigator assessment (RECIST v1.1) in folate receptor positive patients. Secondary objectives include overall survival, safety/tolerability, overall response rate, and disease control rate. Enrollment to the study is currently ongoing.

Exploratory analysis of nibrin in advanced ovarian cancer (AOC) patients treated in the phase III OVA-301 trial.
The results point out the potential importance of nibrin expression in the clinical outcome of patients with advanced ovarian cancer. In particular, high protein expression of nibrin seems to be associated with a worse clinical outcome. Prospective clinical trials evaluating the clinical usefulness of this marker with other standard of care treatments are warranted.

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Darrin Stuart, PhD

Darrin Stuart, PhD

Results of a preliminary study presented at AACR 2013 suggest that using an intermittent dosing strategy with vemurafenib instead of continuous dosing has the potential to overcome the development of resistance in patients with melanoma treated with the drug.

“When vemurafenib was introduced, it was exciting to witness the translation of the discovery of BRAF mutations in melanoma into an effective therapy. However, it was disappointing to see patients stop responding to such a promising therapy after 6 to 8 months of treatment,” said Darrin Stuart, PhD, senior research investigator at the Novartis Institutes for Biomedical Research in Emeryville, California.

BRAF mutations occur in more than 50% of melanoma patients, and vemurafenib extends survival for these patients. However, most of these patients will relapse with lethal drugresistant disease, Stuart said.

A previous study by Stuart and colleagues found that xenografts of melanoma tumors expressing BRAF mutations implanted in experimental mouse models developed resistance to vemurafenib; moreover, the tumors exhibited dependence on vemurafenib to sustain their growth. When the drug was stopped, tumor growth was suspended, and some tumors regressed in the mouse model.

Stuart and colleagues sought to determine whether the tumor drug dependency observed in experimental animal models was also present in humans. They studied 42 patients with vemurafenibresistant tumors. CT scans were available for 19 of these patients who were taken off treatment; 14 of the 19 demonstrated a decrease in the rate of tumor growth once they were no longer taking vemurafenib.

“This is the first evidence that the drug-addicted state that we observed in mouse models may also occur in humans,” he said.

The next step was to implant xenografts of patient-derived BRAF-positive tumors in mice and treat them with vemurafenib either on an intermittent schedule of 4 weeks on/4 weeks off, or on continuous treatment. None of the animals in the intermittent dosing group developed drug resistance.

Continuous dosing maintained the selective pressure required for the few surviving tumor cells to develop resistance, and alternating the selective pressure through intermittent dosing appeared to prevent the evolution and expansion of resistant cells, Stuart said.

At a press conference, Stuart was asked whether the next step for Novartis will be to study intermittent dosing and compare it with continuous dosing in patients. “Novartis is interested in testing multiple approaches that include trying different dosing regimens to using different combinations of drugs with vemurafenib,” he said. “I am not at liberty to say what the company is planning, but I can say we are enthusiastic about the findings I reported at this meeting. Patients derive a clinical benefit from vemurafenib and then develop resistance. Some sort of drug holiday makes sense. I hope people will study this clinically.”


Thakur MD, Fisher R, Salangsang F, et al. Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Presented at: the AACR Annual Meeting 2013; April 6-10, 2013; Washington, DC. Abstract LB-144.

Tumor tissue samples

Tumor tissue samples await analysis for cancer-related genes at the Center for Advanced Molecular Diagnostics at Brigham and Women’s Hospital in Boston.

As the cost of sequencing and analyzing genetic data continues to fall, the nation’s leading cancer centers keep unveiling ambitious new clinical programs and research projects that will change the way every cancer specialist practices. Dana-Farber Cancer Institute, along with Brigham and Women’s Hospital, has launched one of the biggest research programs to date, in which the Boston, Massachusetts, centers seek to make the tumors of every patient with cancer a subject of genetic research.

Other cancer centers, while not broadening the research pool so widely, have deepened it by analyzing multiple tumor samples from each patient or conducting full-genome sequencing of both tumor samples and healthy tissue in tested patients.

These research projects supplement rapidly evolving protocols for clinical care. The tumors of most patients at most major facilities now receive some form of genomic testing to guide treatment. And that testing keeps getting more detailed.

For oncologists, hematologists, and other specialists who treat patients with cancer outside academe, these trends portend more than just an avalanche of studies that will have to be read. They portend a whole new age, albeit one that’s still a bit hazy.

Gordon B. Mills, MD, PhD

Gordon B. Mills, MD, PhD

“Genetic analysis has already changed cancer care at every practice, and we’ve only seen the tiniest tip of the iceberg,” said Gordon B. Mills, MD, PhD, who chairs the Department of Systems Biology and holds the Olga Keith Weiss Distinguished University Chair for Cancer Research at The University of Texas MD Anderson Cancer Center in Houston.

“But I think we have a little work to do before we know how we can best use these new tools,” he said. “Different cancer centers are trying different things, which will help us figure out what works and what doesn’t, and what all cancer specialists should eventually be doing.”

Sequencing Costs Plummeting

Ever since the Human Genome Project resulted in the full sequencing of the first human genome in 2003, technological advances have increasingly enabled researchers to explore the genetic underpinnings of cancer at a decreasing cost.

“The ability to sequence an individual’s entire genome as well as the patient’s tumor genome is now a feasible enterprise at a cost and speed that was unthinkable even five years ago,” noted Boris Pasche, MD, PhD, of the University of Alabama in Birmingham, and Devin Absher, PhD, of the HudsonAlpha Institute for Biotechnology in Alabama, in an editorial in the Journal of the American Medical Association last year.1

Indeed, it took 10 years and more than $2 billion to sequence the first human genome. Today, whole-genome sequencing costs from approximately $10,000 to $35,000 per human genome, and the National Institutes of Health (NIH) $1000 genome target is within the realm of possibility.2

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