Preclinical Results Validate Lpathomab As A Potential Future Treatment for Ovarian Cancer

“Lpath, Inc. … , the category leader in bioactive-lipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies …”

“Lpath Presents Compelling New Preclinical Results of Its Anti-Cancer Drug Candidate, Lpathomab(TM), at the AACR 100th Annual Meeting –

New In Vivo and In Vitro Results Provide Further Validation of Lpathomab as Potential Treatment for Cancer

SAN DIEGO, CA, Apr 20, 2009 (MARKET WIRE via COMTEX)Lpath, Inc. (OTCBB: LPTN), the category leader in bioactivelipid-targeted therapeutics, reported compelling new in vivo and in vitro results relating to its preclinical drug candidate, Lpathomab, in various ovarian cancer studies. The results were presented today by Lpath scientists at the 100th Annual Meeting of the American Association for Cancer Research (AACR) in Denver, Colorado.

Lpathomab is a monoclonal antibody that binds to the bioactive lipid lysophosphatidic acid (LPA) and acts as a molecular sponge to absorb LPA, thereby neutralizing LPA-mediated biological effects on tumor growth, angiogenesis, and metastasis. LPA has been associated with a variety of cancer types, but the correlation with ovarian cancer and breast cancer has been particularly strong.

Using the human ovarian cell line called SKOV3, Lpath’s preclinical studies demonstrated Lpathomab significantly reduced IL-8 and IL-6 cytokine release in SKOV3-conditioned media and blocked tumor-cell migration triggered by LPA (both IL-8 and IL-6 promote tumor angiogenesis and metastasis). More important, Lpathomab inhibited the progression of SKOV3 tumor cells when injected into the peritoneal cavity of mice and reduced levels of pro-metastatic factors in these animals.

Lpathomab also reduced neovascularization (new blood-vessel growth) in two classical angiogenic models and showed preliminary anti-metastatic activity when tested in a classical experimental metastasis model.

According to Roger Sabbadini, Ph.D., Lpath’s founder and chief scientific officer, ‘In view of these promising preclinical results, we believe Lpathomab has the potential to augment the efficacy of current ovarian cancer therapy by blocking the growth-promoting, angiogenic, and metastatic effects of LPA.’

About Lpath

San-Diego-based Lpath, Inc. is the category leader in bioactive-lipid-targeted therapeutics, an emerging field of medical science whereby bioactive signaling lipids are targeted for treating important human diseases. ASONEP(TM), an antibody against Sphingosine-1-Phosphate (S1P), is currently in a Phase 1 clinical trial in cancer patients and also holds promise against multiple sclerosis and various other disorders. ASONEP is being developed with the support of partner Merck-Serono as part of a worldwide exclusive license. A second product candidate, iSONEP(TM) (the ocular formulation of the S1P antibody), has demonstrated superior results in various preclinical models of age-related macular degeneration (AMD) and retinopathy and is in a Phase 1 clinical trial in wet-AMD patients. Lpath’s third product candidate, Lpathomab(TM), is an antibody against lysophosphatidic acid (LPA), a key bioactive lipid that has been long recognized as a valid disease target (cancer, neuropathic pain, fibrosis). The company’s unique ability to generate novel antibodies against bioactive lipids is based on its ImmuneY2(TM) drug-discovery engine, which the company is leveraging as a means to expand its pipeline. For more information, visit www.Lpath.com …”

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Liposomal siRNA — Genetic On/Off Switches That Target Ovarian Cancer Through the Trojan Horse Effect

Use of Liposomal siRNA to Target Ovarian Cancer Protein Known as “Interleukin-8 (IL-8)”

“A protein that stimulates blood vessel growth worsens ovarian cancer, but its production can be stifled by a tiny bit of RNA wrapped in a fatty nanoparticle, a research team led by scientists at The University of Texas M. D. Anderson Cancer Center reports in the Journal of the National Cancer Institute.

The protein IL-8 is a potential therapeutic target in ovarian cancer,’ said senior author Anil Sood, M.D., professor in the M. D. Anderson Departments of Gynecologic Oncology and Cancer Biology.

The paper demonstrates that high IL-8 expression in tumors is associated with advanced tumor stage and earlier death for ovarian cancer patients. Lab experiments and research in a mouse model show that short interfering RNA (siRNA) can cut IL-8 expression, reducing tumor size by attacking its blood supply.

‘This comprehensive analysis – with human data, animal data and lab experiments to highlight the molecular mechanisms involved – helps us develop the new targets needed for a more effective approach against ovarian cancer,’ Sood said.

Interleukin-8 is overexpressed in many types of cancer and has previously been shown to promote tumor growth, new blood vessel growth known as angiogenesis, and metastasis, the spread of cancer to other organs. ‘In the long run, this research will have applications in other cancers as well,’ Sood said.

His research focuses on ovarian cancer, for example, while senior co-author Menashe Bar-Eli, Ph.D., professor in M. D. Anderson’s Department of Cancer Biology, examines IL-8’s role in melanoma.

Impact on survival

Ovarian cancer is often detected in late stages. Initial treatment includes surgery and taxane- or platinum-based chemotherapy regimens that keep the cancer at bay for a time in most patients. Recurrence is common and often lethal.

To examine IL-8’s role in ovarian cancer, the researchers analyzed tumors from 102 patients diagnosed and treated between 1988 and 2006 at M. D. Anderson and the University of Iowa. Of those, 43 had tumors with high levels of IL-8 and 59 had low levels. The median survival of those with high IL-8 tumors was 1.62 years, compared with 3.79 years for those with low expression of the protein.

All 43 tumors with high expression of IL-8 were of high grade and 42 of 43 were advanced, either stage III or IV tumors. By comparison, 10 of 59 tumors with low IL-8 expression were early stage tumors and six were of low grade.

Shrinking tumors

Genes transcribe single strands of RNA that in turn are ‘read’ by ribosomes to produce proteins. siRNAs are short, double-stranded bits of RNA capable of halting that process. The team confirmed in a lab experiment that a specific siRNA silences IL-8 and then tested it against two lines of ovarian cancer in a mouse model.

Sood, Gabriel Lopez-Berestein, M.D., professor in M. D. Anderson’s Department of Experimental Therapeutics, and colleagues are building an arsenal of siRNAs capable of silencing genes that produce cancer-promoting proteins. They packaged siRNA that stymies IL-8 into a small ball of fat known as a liposome, a combination they developed to overcome a problem – siRNA is hard to deliver to tumors.

Tumors shrank by a median of 32 percent and 52 percent in the two cancer lines among mice that received injections of the IL-8 siRNA liposome compared to those receiving control siRNA or empty liposomes.

Mice that got both the IL-8 siRNA plus the taxane-based chemotherapy drug docetaxel [Taxotere®] had median tumor weight reduction of 90 percent and 98 percent in the two cell lines. Mice with control siRNA plus docetaxel saw reductions of 67 and 84 percent.

Finally, they tested the approach in mice with an ovarian cancer cell line known to be resistant to taxane-based drugs such as docetaxel. IL-8 siRNA alone reduced the size of these tumors by 47 percent, and when combined with docetaxel reduced tumor size by 77 percent, suggesting that the combination re-sensitizes a resistant tumor to taxanes.

The team gauged the impact of IL-8 siRNA on tumor blood supply by measuring the density of blood vessels in the tumor. The IL-8 siRNA alone reduced blood vessel density by 34 percent and 39 percent in two cancer lines.

Clinical Prospects

‘These are encouraging results. We want to move one of our siRNA agents into the clinic to test its potential for therapy,’ Sood said, ‘and then in the longer term, we’ll consider moving additional siRNA agents into the clinical arena.’

The IL-8 siRNA liposome is the third developed by Sood’s and Lopez-Berestein’s team. Two others target the oncoproteins FAK and EphA2. The EphA2 siRNA liposome is closest to Phase I clinical trial, with required toxicology studies nearly complete. A clinical trial could begin within a year.

Methods used to inject siRNA in high volumes for research purposes are impractical for human therapy. Sood and Lopez-Berestein developed the liposomal approach to ensure that the siRNA reaches the cell intact so it can silence the targeted gene. Their research has shown that the liposome penetrates deeply into cells to deliver its siRNA.

Research reported in JNCI was funded by grants from the National Cancer Institute of the National Institutes of Health, including M. D. Anderson’s Specialized Program of Research Excellence in Ovarian Cancer; the Ovarian Cancer Research Fund, Inc.; and the Zarrow Foundation.”

Quoted Source: [“Researchers Identify and Shut Down Protein that Fuels Ovarian Cancer, M. D. Anderson-led team pinpoints blood vessel promoter’s role and targets it with siRNA,” M.D Anderson News Release, dated February 26, 2008]. See also “Effect of Interleukin-8 Gene Silencing With Liposome-Encapsulated Small Interfering RNA on Ovarian Cancer Cell Growth;” Merritt,W.M., Lin,Y.G., Spannuth,W.A., Fletcher,M.S., Kamat,A.A., Han,L.Y., Landen,C.N., Jennings,M., Geest,K., Langley,R.R., Villares,G., Sanguino,A., Lutgendorf,S.K., Lopez-Berestein,G., Bar-Eli,M.M., Sood, A.K.; Journal of the National Cancer Institute 2008 100(5):359-372.

Use of Liposomal siRNA to Target Ovarian Cancer Protein Known as “Focal-Adhesion Kinase (FAK)”

Recent work reported in October 2006 by Dr. Anil Sood at M.D. Anderson involved the use of a targeted “siRNAliposome in mice to identify and correct defective ovarian cancer cells. M. D. Anderson researchers used siRNA (which acts as a genetic “on/off” switch) to target an ovarian cancer protein known as focal-adhesion kinase (FAK), which is present in all ovarian cancer cells. FAK helps ovarian cancer cells survive and spread. The siRNA was rolled into a liposome – a ball of fat so small that its dimensions are measured in nanometers (billionths of a meter). Because of their tiny size, these liposomes have no problem traveling through the blood supply into cells that make up tumors through the so-called “Trojan Horse” effect. To test how well it worked, mice that were implanted with human ovarian tumors were given injections of the therapy for three to five weeks. The mice ovarian tumors experienced a 44% to 72% reduction in weight. Adding chemotherapy to the treatment boosted tumor weight reduction to the 94% to 98% range. The next step for the FAK siRNA liposome is testing for toxicity prior to studies in human patients.

Source: [ “Novel Therapy Shrinks Ovarian Tumors in Mice, Genetic Fragments Turn Off Cancer Growth Switch,” Cancer Newsline, October 2006, M.D. Anderson Cancer Center, University of Texas.]

Use of Liposomal siRNA to Target the Ovarian Cancer Kinase Known as “EphA2”

In an earlier in vitro studies, Anil Sood, M.D. et. al. demonstrated that when EphA2-targeting siRNA was combined with paclitaxel [Taxol®], tumor growth was dramatically reduced compared with treatment with paclitaxel and a nonsilencing siRNA. These studies show the feasibility of siRNA as a clinically applicable therapeutic modality.

Source: [“Therapeutic EphA2 Gene Targeting In vivo Using Neutral Liposomal Small Interfering RNA Delivery;” Landen,C.N., Chavez-Reyes, A., Bucana, C., Schmandt, R., T. Deavers, M., Lopez-Berestein, G. and Sood, A.K., The University of Texas M.D. Anderson Cancer Center, Houston, Texas; Cancer Research 65, 6910-6918, August 1, 2005.

Comment: The ultimate use of siRNA to treat ovarian cancer in humans holds future promise. Ovarian cancer survivors should monitor the development of this liposomal siRNA form of treatment because its use in human clinical trials could occur in the near future, assuming that pre-clinical trial toxicity tests demonstrate safety. Anil Sood, M.D. has developed the liposomal siRNA for IL-8, FAK, and EphA2. It is reported that human clinical trials with respect to the EphA2 siRNA treatment will begin within 12 months.