Disease Background
Malignant gliomas are highly invasive and neurologically destructive tumors, whose most aggressive manifestation is glioblastoma (GBM). GBM is an anaplastic, highly cellular astrocytoma, with high proliferation indices, microvascular proliferation and focal necrosis. GBM prognosis remains dismal. Survival time is less than 2 years for the majority of patients. Current therapeutic options for GBM include surgery, radiotherapy and chemotherapy. Concurrent temozolomide and radiotherapy has now become the new standard of care for patients with newly diagnosed GBM.
Melanoma, on the other hand, is a malignant neoplasm of melanocytes and is the most deadly form of skin cancer. When melanoma is detected in its early stages it is curable, but once advanced it is very difficult to treat. The most common sites of metastases are the skin and subcutaneous tissue, lung, liver, small intestine, pancreas, heart, brain and spleen. With visceral metastasis the median survival from time of diagnosis is 7.5 months. Surgical excision and radiotherapy may be the treatment of choice for certain patients. Advanced and metastatic disease may require treatment with chemotherapy or immunotherapy, although the success rates in metastatic melanoma are quite low.
Finally, thyroid cancer is a malignant neoplasm of the thyroid gland. There are four types of thyroid cancer, differing in histology, prevalence, treatment, and outcome: Papillary (the most common type); Follicular (a well-differentiated, slowly growing type); Medullary (a rare, familial type); and Anaplastic (a rare, aggressive type with very poor prognosis). Surgery and radioactive iodine followed by TSH suppression by thyroxine therapy is commonly used to treat thyroid carcinomas.
Market Opportunity
Glioblastoma is the most common primary brain tumors in the adults. The incidence for this cancer type is two to three cases per 100,000 population per year and prognosis remains dismal.
Melanoma of the skin is the sixth most common cancer type reported in US. The incidence of melanoma continues to increase despite public health initiatives to promote protection against sun’s harmful effects.
Thyroid cancer is the most common endocrine malignancy, with 33,500 new cases of thyroid cancers estimated to be diagnosed in the U.S. in 2008. Once thyroid cancer metastasizes to distant sites and is no longer amenable to radioactive iodine therapy or surgery, expected survival declines rapidly. The only FDA-approved therapy for these patients is doxorubicin.
All three cancer types, malignant gliomas, melanoma and thyroid cancer, constitute unmet medical needs, demanding novel safe and effective treatments.
Mechanism of Action
BVA-501 is an antibiotic marketed in Europe and the US with an excellent safety profile. At Biovista, we have discovered that BVA-501 inhibits the proliferation of malignant glioma, melanoma and thyroid cancer cells. BVA-501 inhibits mitochondrial protein synthesis, and, therefore, inhibits cell proliferation. Inhibition by BVA-501 of mitochondrial protein synthesis results in reduced functionality of the respiratory chain, which in turn leads to inhibition of tumor cell growth and proliferation.
The increased blood-brain-barrier permeability of BVA-501 makes it particular relevant to the treatment of malignant gliomas, which are located in the Central Nervous System (CNS), and of melanoma and thyroid cancer with CNS metastases.
Results to Date
BVA-501 was studied on the growth of 4 selected human melanoma, human glioblastoma and human thyroid cancer cell lines.
Cells were plated in triplicate. At 24 hours post-seeding, the cells were treated with different concentrations of the test compounds for 72 or 120 hours. Paclitaxel (100 nM) was included as a positive control, and 0.5% DMSO (vehicle) was used as a negative control. Cell viability was determined using the CellTiter-Blue® Assay. Data collected were plotted as dose response curves for IC50 (half maximal inhibitory concentration) determination (Figure 1). The maximum inhibition and IC50 obtained for the above mentioned cell lines are presented in Table 1.
| Cell Line | IC50 | Concentration at maximum inhibition | BVA-501 Maximum inhibition (%) | Paclitaxel (0.1uM) Maximum inhibition (%) | Statistical significance of BVA-501 vs Non-treated (p) |
|---|---|---|---|---|---|
| HT-144 (Melanoma) | 500uM | 1mM | 90.7 | 86.9 | 0.00250 |
| A172 (Malignant glioma) | 600-700uM | 1mM | 81.8 | 92.9 | 6*10-6 |
| C32 (Melanoma) | N/A | 1mM | 26.1 | 90.8 | 0.000720 |
| SW-579 (Thyroid Cancer) | N/A | 412uM | 14.5 | N/A | 0.0490 |
Conclusions
BVA-501 has shown activity in a number of cancerous cell lines (malignant glioma, melanoma and thyroid cancer). Together with its favorable pharmacokinetics, good blood-brain-barrier penetration and established safety profile, these results make BVA-501 a good candidate for further evaluation in combination with other chemotherapeutic compounds in these oncology indications.
Intellectual Property
The use of BVA-501 in the new indications is protected by US provisional patent applications, which are currently in progress.
Licensing Opportunity
Our business model is based on licensing and joint-venture agreements for the development of repurposed drugs. If you are interested in exploring licensing or joint development opportunities please contact us at bd{at}biovista.com.