Sunday, March 6, 2011

Marina Biotech Finds Success with Local Bladder Cancer Approach

Marina Biotech this week reported pre-clinical data supporting the use of local, intravesicular siRNA delivery for the treatment of nonmuscle invasive bladder cancer. The publication in Molecular Therapy comes weeks after this early-stage program was partnered with Swiss pharmaceutical Debiopharm which will be responsible for funding the rest of the development.

According to the National Cancer Institute, there are about 70,000 new cases of bladder cancer in the US alone, most of them related to smoking. Because bladder cancer typically starts at the epithelium lining exposed to the urine, simple surgical resection is often sufficient to stop the disease in its tracks. Unfortunately, in some cases the cancer recurs and progresses into a more aggressive, muscle-invasive form of cancer contributing to the 14,700 deaths from bladder cancer annually (US number). Current strategies to prevent recurrence include the instillation of immuno- and chemotherapeutics into the bladder. When this fails, the bladder often has to be removed. Clearly, more treatment options are needed to limit the progression of bladder cancer into the more aggressive forms and maybe also to provide an alternative for bladder removal once more aggressive cancers have developed.

In the present study, Seth and colleagues first screened a range of RNAi triggers against the cancer-related genes polo-like kinase 1 (PLK1) and survivin and were able to demonstrate that Marina’s usiRNA chemistry platform allows for very satisfactory knockdown efficacies with IC50 values in the 10 to 30pM range (bladder cancer cell lines in tissue culture). This triggered widespread apoptosis and, in the case of PLK1, a strong reduction in cell viability. The data therefore add to the notion that PLK1, incidentally also the target in Tekmira’s phase I clinical program TKM-PLK1, may be the single-most promising RNAi cancer target, a view apparently shared by Marina scientists as evidenced in the Discussion part of the paper. Nevertheless, survivin may still be a highly desirable drug target for sensitizing cancer to chemo- and radiation therapies.

The selected siRNAs were then formulated into positively charged multilamellar liposomes of around 100nm. Due to the negatively charged proteoglycan-rich urothelium, a formulation with a lipid containing a guanidinium group was deemed particularly promising in being able to penetrate the 6-7 cell-layered urothelium. Accordingly, these formulations, when instilled into the bladder, were able to very efficiently suppress the growth of nonmuscle invasive bladder cancers in mouse models of the disease. Although equally highly efficient in vivo knockdowns were reported, 90-95% with 1mg/kg (relative to body weight), in my mind there are still some unanswered questions as to how much of that merely reflected the reduction in the size of the tumor.

In terms of safety, no untoward reactions to the formulations were reported. One important reason for this should be the lack of systemic exposure from such treatment. The authors also stated that they were not able to find evidence of innate immune stimulation despite careful investigation. Ideally this analysis would have included a positive control, but then again, also taking into account the 5’ RACE analysis for sequence-specific target cleavage, the overall evidence strongly supports that RNAi knockdown was a main contributor to the in vivo efficacy. Actually, in the case of bladder cancer, having a bit of local immune stimulation may very well be a good thing as I was surprised to learn that bathing the bladder with a solution containing the Calmette-Guerin bacterium (BCG), the famous vaccine against tuberculosis, is part of the current standard of care for superficial bladder cancer and is thought to work by stimulating the immune system. Who knows, Marina may even want to adapt BCG to trans-kingdom RNAi for bladder cancer to combine the RNAi and BCG mechanisms of action into a single agent.

Study Adds yet Another Indication Suitable for Current RNAi technologies

Marina Biotech has made it into an art to select development programs amenable to their current technologies. Given the challenges of systemic RNAi delivery, in a relatively short period of time, the company has already identified and progressed three cancer applications where local approaches can probably be used: familial adenomatous polyposis (FAP; ingested trans-kingdom RNAi), bladder cancer (intravesicular LNP), and most recently malignant ascites (intraperitoneal LNP). Together with developments elsewhere in the field, this clearly shows that the time for RNAi Therapeutics is Now: a range of solid cancers (e.g. liver, lung, FAP, bladder, melanoma), hypercholesterolemia, hemorrhagic fever viruses (Ebola, Marburg), TTR amyloidosis, PHN, AMD, Huntington’s disease etc etc.

3 comments:

Anonymous said...

Dirk


I did not read the paper, but I am assuming these were all rodent tests and not human. If so, who cares. It is the human model that counts and gets the funding.

tettrazini said...

Mentioned as a potentail target was survivin. Lilly is in Phase 2 with an antisense survivin inhibitor licensed from ISIS.

Matt said...

While results in humans are indeed what count in terms of getting significant funding and, ultimately, FDA approval, the rodent model is recognized as being quite predictive of effects in humans. This is an excellent piece of science and I congratulate MRNA's scientists on this important accomplishment.

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