Two advances in glioblastoma
MADISON, Wis. and BUFFALO GROVE, Ill.—Cellectar Biosciences Inc., a clinical stage biopharmaceutical company developing innovative agents for the detection and treatment of cancer, announced publication of the first peer-reviewed proof-of-principle study of a new class of fluorescent alkylphosphocholine analogs for fluorescence-guided glioma surgery in Neurosurgery, official journal of the Congress of Neurological Surgeons. This study is featured on the cover of the February 2015 issue, and demonstrates that the fluorescent cancer-selective CLR1501 and CLR1502 agents successfully provide visualization of glioma cancer cells with high fidelity, and suggest their practical and promising potential to optimize tumor surgery.
Cancer surgeons are challenged to better discriminate cancer cells from normal tissue and are exploring the use of fluorescence agents to optimize tumor visualization and maximize safe surgical resection. Using its highly selective cancer-targeting phospholipid ether (PLE) technology, Cellectar has developed CLR1501 and CLR1502 as novel tumor-selective fluorescent agents to illuminate cancer cells, in vitro and in vivo respectively, thereby distinguishing cancer from normal tissue during diagnostic, staging, debulking and curative cancer surgeries.
The study's objectives were to confirm CLR1501 and CLR1502 cancer-cell selectivity in glioblastoma models, and to quantify their fluorescent signals that distinguish tumor from normal brain in comparison to 5-ALA, an agent commercially available in the European Union for image-guided surgery but not approved for routine use in the United States. This study showed that the CLR1501 tumor-specific fluorescence signal is similar to 5-ALA, and that CLR1502 has a superior tumor- to-brain fluorescence ratio.
"There is compelling evidence from a growing number of peer-reviewed studies that demonstrate the ability of Cellectar PLE agents to selectively target cancer cells," said senior author, John S. Kuo, M.D., Ph.D., associate professor of neurological surgery, director of the Comprehensive Brain Tumor Program and chair of the Carbone Cancer Center CNS Tumors Group at the University of Wisconsin-Madison. "Using fluorescent Cellectar PLE agents for real-time, intraoperative discrimination of cancer from adjacent normal tissue promises to optimize tumor removal and preserve critical normal tissue. Since Cellectar PLE technology successfully targets many different cancers, CLR1502 has great potential to significantly advance tumor fluorescence-guided surgery and improve clinical outcomes for many surgically managed cancers."
Cellectar plans to initiate a Phase I proof-of-principle clinical trial of CLR1502 in patients undergoing breast cancer surgery later in 2015.
Elsewhere, Buffalo Grove, IL-based RestorGenex Corp., a specialty biopharmaceutical company focused on developing products for oncology, ophthalmology and dermatology, presented scientific data on RES-529 for the treatment of glioblastoma multiforme (GBM) at the Keystone Symposia Series on PI 3-Kinase (PI3K) signaling pathways. The presentation titled "Validation of RES-529, a novel TORC1/TORC2 allosteric dissociative PI3K inhibitor in glioblastoma multiforme" was presented on January 16, 2015. RES-529 is a proprietary first-in- class PI3K/Akt/mTOR pathway inhibitor that is capable of dissociating both TORC1 and TORC2.
"The data presented help to understand the use of RES-529 and the validity of targeting the TORC1 and TORC2 protein complexes in a dissociative manner for GBM. This, and other work, supports the rationale for RestorGenex's plans to advance RES-529 into clinical trials in GBM," said David Sherris, Ph.D., chief scientific officer of RestorGenex.
The poster presentation discussed in-vitro and in-vivo data from preclinical studies evaluating RES-529 in GBM, a disease in which elevated expression of the PI3K is commonly seen. In the first study, RES-529 demonstrated an ability to inhibit signal transducers of the PI3K pathway that are controlled by TORC1 and TORC2. This mechanism was shown in a variety of tumor cells, including cells that have lost tumor suppressor PTEN.
In a second study, RES-529 was compared with two catalytic inhibitors of the PI3K pathway currently in the clinic; a combination PI3K/mTOR agent and a combination PI3K/Akt agent. In these experiments, RES-529 showed a 20- to more than 100-fold increase in activity above the other inhibitors. In addition, RES-529 was shown to inhibit tumor cell survival up to two orders of magnitude over that of a rapamycin analog PI3K inhibitor (TORC1 dissociative inhibitor approved by the FDA for select tumor types) in a tumor cell model known to show resistance to TORC1 inhibition.
A third study was presented that demonstrated RES-529 penetrates the blood-brain barrier. This was supported by efficacy data of RES-529 in an orthotopic GBM xenograft model where RES-529 showed an improvement in survival vs. control, similar to radiation treatment. When utilized in combination with radiation, RES-529 showed synergy extending survival above that of either RES-529 or radiation alone.
"GBM is a disease with a very poor prognosis. Less than 10 percent of newly diagnosed patients survive 5 years. Current standard of care extends overall survival only by approximately 13 to 15 months, and thus there is a clear unmet medical need for novel treatments to treat brain cancer," said Stephen M. Simes, chief executive officer of RestorGenex.
Cellectar Biosciences is developing agents to detect, treat and monitor a broad spectrum of cancers. Using a novel phospholipid ether (PLE) analog platform technology as a targeted delivery and retention vehicle, Cellectar's compounds are designed to be selectively taken up and retained in cancer cells including cancer stem cells. With the ability to attach both imaging and therapeutic agents to its proprietary delivery platform, Cellectar has developed a portfolio of product candidates engineered to leverage the unique characteristics of cancer cells to "find, treat and follow" malignancies in a highly selective way.
RestorGenex is a specialty biopharmaceutical company focused on developing a portfolio of first-in-class therapeutic products to treat diseases across the ophthalmologic, oncologic and dermatologic space. RestorGenex's lead product is a novel PI3K/Akt/mTOR pathway inhibitor which has completed two Phase 1 clinical trials for age-related macular degeneration and is in pre-clinical development for glioblastoma multiforme. The current pipeline also includes a "soft" anti-androgen compound for the treatment of acne vulgaris. RestorGenex's novel inhibition of the PI3K pathway and unique targeting of the androgen receptor show promise in a number of additional diseases, which the company is evaluating for the purpose of creating safe and effective treatments and innovative therapies.