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Alfacell Researchers Report Data Indicating Lead Cancer Drug Candidate Targets RNAi

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A team of investigators from Alfacell and the New York Medical College this week published a report showing that the company’s lead drug candidate, Onconase, can inhibit the function of siRNAs.
 
According to a company official, the data, which appears in the Oct. 1 issue of Cell Cycle, suggest that the compound may have potential as a microRNA-targeting diagnostic tool. However, the early nature of the data, along with Alfacell’s financial troubles, may slow the development of such a tool, she said.
 
“Onconase itself targets microRNAs,” Alfacell CEO and founder Kuslima Shogen told RNAi News this week. “I envision this could be a very important diagnostic tool … in assessing tumor types, which of the microRNAs are being affected [in the malignancy], and which drugs would be effective against a particular tumor type.”
 
According to the new research, one of the intracellular RNA targets of Onconase is siRNA, likely within the RNA-induced silencing complex. Potentially, miRNA signatures in tumor tissues could be compared with signatures from tumor samples that have been treated with Onconase, providing a snapshot of which of the small, non-coding RNAs are dysregulated by the disease.
 
But developing the drug as a diagnostic reagent may not happen any time soon. Shogen noted that Alfacell would likely need a partner to help develop Onconase for diagnostic applications since the field is one in which the company does not have any expertise. At the moment, however, “it’s a little too early” to be actively seeking partnerships, she said.
 
“But as we gather more information on microRNAs and … as more data becomes available to us, clearly there will be a much clearer picture of how best to use this compound as a diagnostic” and proceed with partnership discussions, she added.
 
At the same time, Alfacell is facing economic uncertainty: With its stock hovering around $0.52 per share, just above a 52-week low of $0.35, the company this week reported increased fiscal fourth-quarter losses on greater expenses.
 
As of July 31, the company had $4.7 million in cash and cash equivalents, enough to support its current level of operations only through the fourth quarter of fiscal 2009, it said. And in September, Alfacell announced that it had hired financial advisors to explore “strategic alternatives,” including the possible sale of the company.
 
’Unclear Targets’
 
Onconase, known generically as ranpirnase, is a ribonuclease extracted from the egg of the amphibian Rana pipiens, where it is believed to play a role in development and host defense, according to Alfacell. Given its ability to trigger apoptosis, inhibit tumor growth, and enhance cell sensitivity to chemotherapeutics, the compound is currently in clinical trials for a variety of cancers.
 

“I envision this could be a very important diagnostic tool … in assessing tumor types, which of the microRNAs are being affected [in the malignancy], and which drugs would be effective against a particular tumor type.”

While it is known that Onconase targets intracellular RNA, “it is unclear … which RNA specific within the cell are … targets whose destruction may explain why [the drug] exerts it cytostatic and cytotoxic effects that are preferential to tumor cells,” the researchers wrote in Cell Cycle. “We previously postulated that the antitumor activity … and the observed synergisms with other anti-tumor modalities at least in part may be mediated by targeting RNA interference.”
 
To validate their hypothesis, the investigators aimed to see whether the drug could affect the gene-silencing properties of an siRNA targeting the glyceraldehyde 3-phosphate dehydrogenase gene in vitro.
 
According to the Cell Cycle paper, A549 cells were transfected with siRNAs against GAPDH, which resulted in significant inhibition of the enzyme in “nearly all cells, regardless of the cell cycle phase” compared with untreated cells. Cells transfected with a negative control siRNA showed the same level of GAPDH as untreated cells.
 
However, when siRNA-transfected cells were treated with Onconase, expression of GAPDH was restored, the researchers wrote. “The negative control siRNA had no effect on GAPDH expression, indicating that the procedure of the transfection and the non-sequence-specific effects of the siRNA did not play a role in the observed silencing of the gene expression,” they noted.
 
As for whether Onconase targets siRNAs in RISC, the investigators wrote that since the drug silenced GAPDH expression after it was added into cultures that had been transfected with siRNA 24 hours prior, “it is likely that [Onconase] targeted siRNA that was already assembled within RISC.”
 
Onconase’s apparent RNAi-targeting abilities, the researchers added, may help explain the drug’s preferential cytotoxicity to tumor cells and its ability to sensitize cells to cancer treatments in light of the growing body of literature linking miRNA to malignancies.
 
“Many microRNAs are extensively involved in pathogenesis of both leukemias and solid tumors, and they promote neoplastic growth by controlling expression of protein-encoding tumor suppressors and oncogenes,” they wrote. “By targeting RNAi, thus, [Onconase] may be more effective in suppression growth of tumors, [rather] than normal, cells.”
Additionally, cell resistance to anticancer drugs has been shown to be mediated by miRNAs, they added. The propensity of Onconase “to target microRNAs involved in providing cell resistance may thus provide explanation for the synergistic effects observed when [the drug] was combined with a variety of anti-tumor modalities characterized by diverse mechanisms of action.”

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