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Each year nearly 20,000 people in the U.S. are diagnosed with primary brain cancers (with a similar number in Europe), according to NCI/NIH statistics, with Schering-Plough's (NYSE:SGP) Temodar (temozolomide or TMZ is classified as a DNA-methylating chemotherapy drug) given to nearly every patient with a diagnosis of GBM (the most common and aggressive form of brain cancer). Newly diagnosed individuals with GBM typically undergo surgery (if possible) to remove the tumor, followed by radiation and chemotherapy with a median survival outcome of about 10-12 months.
In early May, Roche (OTCQX:RHHBY) announced that the FDA granted accelerated approval of Avastin (bevacizumab) for people with glioblastoma (GBM) that have progressive disease following prior therapy. Following initial treatment with chemotherapy and radiation, more than 90% of patients with GBM experience recurrence of the disease and few effective treatment options are available. In addition, Eisai (OTCPK:ESALY) markets the Gliadel Wafer, which is indicated in patients with newly diagnosed high-grade malignant glioma as an adjunct to surgery and radiation as well as in patients with recurrent GBM as an adjunct to surgery.
Below is a selection of small and micro-cap stocks from my Cancer Diagnostic & Therapeutic (Dx/Tx) Micro-Cap Index that are involved in research activities to improve the treatment of brain cancer. In addition, three of the companies profiled below are among 10 stocks in the Mentor Capital Cancer Immunotherapy Index (MNTR.pk).
Northwest Biotherapeutics (NWBO) is developing DCVax-Brain as an experimental autologous (patient-derived) cellular therapy that is designed to create a specific immune response against a patient’s cancer. DCVax-Brain utilizes a patient’s own dendritic cells (DC), and an extract of the patient’s own tumor cells to achieve an immune response.
In early April, Ark Therapeutics (OTC:ARKTF) announced the first update of results for its Cerepro Phase 3 clinical trial as a novel gene-based medicine for the treatment of operable malignant glioma. The study is being conducted to confirm the safety and efficacy of Cerepro in patients with operable high grade glioma (brain cancer) against current standard treatment options, including (1) surgery and radiotherapy or (2) surgery and radiotherapy followed approximately 40 days post-op by temozolomide.
Significance levels associated with the main data have improved in the update analyses and 29 patients have yet to reach a primary endpoint event (versus 53 previously), of which 18 have been treated with Cerepro and 11 received standard of care treatment. Data suggests improved overall survival in patients receiving Cerepro after about 500 days with 56 patients in the trial still alive. A marketing approval application (MAA) in Europe for Cerepro was filed with the EMEA in 4Q08 and an opinion from the CHMP is expected during 4Q09.
Cerepro is a novel gene-based product for the treatment of patients with operable high grade glioma and utilizes a well-established adenoviral vector (Ad5) to introduce the gene that causes cells to express a protein called thymidine kinase ("TK"). Following the standard surgery to remove the solid tumor mass, Cerepro is injected through the wall of the cavity left behind by the surgical removal of the solid tumor, into the surrounding healthy brain tissue. In the following days, the healthy cells in the wall of the cavity express TK.
Five days after surgery, the drug ganciclovir (GCV) is given to the patient as part of the overall Cerepro treatment regimen. Neither TK nor GCV is individually active but they react together to produce a substance which destroys cells when they try to divide. Since cell division is a key characteristic of cancer and the normal brain cells are not dividing, cells that try to divide to form a new tumor around the site of the removal of the original tumor are targeted for destruction by the Cerepro treatment.
Exelixis (NASDAQ:EXEL) is co-developing XL184 (BMS-907351) along with Bristol-Myers (NYSE:BMY). A Phase 2 trial of XL184 in subjects with progressive or recurrent GBM in first or second relapse is ongoing. XL184 inhibits MET, VEGFR2, and RET, which are key drivers of tumor formation, growth, and metastasis. The Company is also co-developing XL765 along with Sanofi-Aventis (NYSE:SNY). XL765 targets both PI3K and mTOR, which are key elements in pathways leading to cell proliferation and is currently being evaluated in a Phase 1b/2 trial in combination with Temodar in GBM patients.
ImmunoCellular Therapeutics (IMUC) is a cancer immunotherapy company that is developing therapeutic and diagnostic product candidates taking aim at the root cause of the disease, cancer stem cells (CSCs), based on two distinct technology platforms - active (cancer vaccines) and passive (monoclonal antibodies or mAbs).

This approach is in the early stages of development, but has the potential to become a paradigm-shifting therapeutic approach to the treatment of cancer. CSCs are resistant to standard treatments such as chemotherapy and radiation, but numerous bio-markers on these cells have been identified which can be used to develop targeted mAbs and CSC immunotherapy products.
Although CSCs account for a small proportion of the cells in a given tumor, a growing body of scientific literature suggests CSCs drive the process of tumor growth and recurrence (even after the disease is undetectable and thought to be eradicated). Current therapeutic options such as radiation therapy or chemo target the proliferating cells, which form the bulk of any tumor mass while the CSCs lie dormant and unaffected at the root of the disease. Thus, a non-detectable number of CSCs may persist even after a patient is in remission, leading to the potential for recurrence of the disease.
IMUC’s cancer immunotherapy candidate, ICT-121, is expected to begin Phase I/II clinical testing in humans in early 2010 as an off-the-shelf product (i.e. does not require obtaining cells from the patient as part of the manufacturing process). ICT-121 works by eliciting a targeted T cell immune response specific to MHC class I molecules (which are highly specific to CSCs and cancer cells) and CD133+ cells, since CD133 also occurs on normal cells at reduced levels (e.g. 4,500 copies on a normal cell versus 30,000-180,000 copies on a CSC).
Blockbuster potential exists for ICT-121 targeting an unmet medical need (brain cancer initially, then pancreatic cancer) and is designed for use in combination with the current standard of care (i.e. surgery, chemo, and radiation therapy) to target residual disease as a paradigm-shifting treatment with the goal of completely eradicating the presence of cancer cells and their future recurrence or spread. IMUC is also developing CSC-targeting mAbs for both therapeutic and diagnostic applications in the treatment of cancer.
Celldex Therapeutics (NASDAQ:CLDX) is developing CDX-110 as a cancer immunotherapy product candidate targeting the tumor specific molecule called EGFRvIII, which is a functional variant (tumor-specific) of the epidermal growth factor receptor (EGFR), a protein that has been well validated as a target for cancer therapy (i.e. Erbitux). While originally discovered in GBM, the expression of EGFRvIII has also been observed in various other cancers such as breast, ovarian, metastatic prostate, colorectal, and head & neck cancers.
In collaboration with its partner, Pfizer (NYSE:PFE), Celldex is currently performing a Phase 2 study (the “ACT III” study) of CDX-110 in patients with newly diagnosed GBM. Objectives of the study are to investigate the anticancer activity, impact on survival, and safety of CDX-110 when administered during a 12 month course of maintenance temozolomide chemotherapy and then continuing until disease progression. Approximately 60 patients will receive CDX-110 as part of this study.
The National Cancer Institute’s (NCI) Division of Cancer Treatment and Diagnosis (DCTD) is currently sponsoring a Phase I clinical trial to evaluate dose and safety of Curis Inc.'s (NASDAQ:CRIS) GDC-0449 in medulloblastoma patients up to 21 years of age, as well as a Phase II trial in adult patients with medulloblastoma (a malignant tumor of the cerebellum that represents the most common brain malignancy in children). GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of cell surface receptors and suppressing signaling pathways, which play an important role in tissue growth and may lead to the uncontrolled proliferation of cells if mutations occur.
Peregrine Pharma (NASDAQ:PPHM) is developing Cotara as an experimental treatment for brain cancer that links a radioactive isotope to a targeted monoclonal antibody designed to bind to a specific DNA histone complex that is exposed by dead and dying cells found at the center of solid tumors. This targeting mechanism enables Cotara to bind to dying tumor cells, delivering a radioactive dose to the adjacent living tumor cells and essentially destroying the tumor from the inside out, with minimal radiation exposure to healthy tissue.
In addition to an ongoing Phase 2 trial in India, a dosimetry and dose confirmation trial in GBM patients at leading U.S. academic brain cancer centers is nearing completion. Cotara has been granted orphan drug status and fast track designation for the treatment of GBM and anaplastic astrocytoma by the FDA.
Arno Therapeutics (OTCQB:ARNI) is developing its lead clinical compound (AR-67) as a novel, third-generation camptothecin analogue that inhibits Topoisomerase I activity. AR-67 has demonstrated activity and an excellent safety profile in clinical studies as well as improved pharmacokinetic properties when compared to approved second-generation products, including Hycamtin (topotecan) and Camptosar (irinotecan). The Company expects to begin a Phase 2 study during 2009 for AR-67 in the treatment of GBM.
YM BioSciences (AMEX:YMI) is evaluating its lead anti-cancer compound nimotuzumab (nimo) (an IgG1, humanized epidermal growth factor or EGFR targeting monoclonal antibody or MAb) in 11 Phase 2 and 3 international trials, including three by YMI and eight by its licensees. Nimo is in the same class as Erbitux (cetuximab), but has a better safety profile since it does not cause the severe (Grade 3 or 4) skin rash associated with these types of treatments. The lack of severe skin rash would otherwise be a clear advantage, but in this case the clinical effectiveness of EGFR inhibitors is thought to be linked with the occurrence of this side effect (see the Company's corporate presentation for more details and images of Grade 3 or 4 rash).
The following are expected milestones for nimo clinical data, with the majority representing studies in both children and adults with a variety of brain cancers:
  1. nimo post-marketing data 150 patients in epithelial-derived tumors 3Q09;
  2. nimo Phase 2 first-line NSCLC in 2010;
  3. nimo European final Phase 3 first-line pediatric glioma data in 2010;
  4. nimo European Phase 3 first-line adult glioma data in 2010;
  5. nimo North American Phase 2 recurrent pediatric glioma data in 2010;
  6. nimo esophageal Phase 2 first-line data (Brazil) in 2010;
  7. nimo Phase 2 (Japan) recurrent gastric cancer data possibly in 2010;
  8. recruitment by Oncoscience AG in nimo Phase 3 trial among newly diagnosed pediatric pontine glioma patients is concluded; and
  9. recruitment by Oncoscience AG in a Phase 3 trial for adult GBM grade IV will be completed in 2009.
Lixte Biotech (OTCQB:LIXT) was originally founded as a diagnostics company in 2005 evaluating biomarkers (indicators of disease at the molecular level), but has shifted its focus to cancer drug discovery research that is primarily focused on the development of compounds for malignancies with few effective treatment options - such as certain types of brain cancer (glioblastoma multiforme or GBM, neuroblastoma, and medulloblastoma) and pancreatic cancer.
In early July, Lixte announced that the results of studies characterizing the novel and potent anti-cancer activity and mechanism of action of its lead compound (LB-1.2) both alone and in combination with standard chemotherapy drugs were published in a leading scientific journal, the Proceedings of the National Academy of Sciences. The primary conclusion was that one of the Company's lead compounds appears to inhibit cancer cells by stimulating cancer cells to attempt to grow in the presence of a standard cancer drug and interferes with cancer cell defense mechanisms, with the end result being much greater damage to the cancer than occurs when treatment is limited to the standard anti-cancer drug.
The authors of this study concluded that treatment with the Company's compound LB-1.2 may be a general method for enhancing the therapeutic benefit of a number of standard cancer regimens, not limited to the original targets of brain tumors of adults and children. Based on the positive preclinical results for LB-1.2, Lixte believes its lead compounds have the potential to be used in combination with Temodar (for a similar commercial market opportunity) since nearly all patients with GBM relapse regardless of current treatments and the published study results offer a possible explanation for a synergistic mode of action that must be proven in human clinical trials
One lead compound (LB-1) is the most advanced in the process and Lixte plans to be ready for IND submission in mid-2010. The other lead compound (LB-2.5), which inhibits cancer cells by a different mode of action compared to LB-1, is anticipated to complete its evaluation by the end of 2010. If the Company is able to achieve a strategic partnership and funding from an established pharmaceutical company to co-develop its compounds, the development process is expected to occur more quickly since these two lead compounds are well characterized with regards to their activity and mechanism of action. The encouraging preclinical results for LB-1.2 as an add-on treatment for brain cancer, the unmet medical needs for effective brain and pancreatic cancer treatments, and the pending patents for Lixte’s lead compound should increase the awareness of the Company’s research and hopefully result in funding to expedite the process.
Disclosure: Long IMUC.OB, MNTR.PK
Source: Small Cap Stocks Battling Brain Cancer