The present invention discloses small molecules 70-folds more effective in vitro than temozolomide on patient-derived GB tumoral cell lines, and with efficacy comparable to that of bevacizumab, but with improved drug-like characteristics. Compounds identified so far are at the “hit stage”. The inventors’ experience in hit identification utilizing all modern techniques, including both the chemistry and the biology competences led to the identification and refinement of high-quality hit series.
Patent Status
PENDING
Priority Number
EP21201359
Priority Date
07/10/2021
License
EUROPE
Market
The global GB drugs market is expected to reach $2.3 billion by 2029, expanding at a CAGR of 12.7% during the forecast period, driven by rising geriatric population, growing incidence cases, and a strong pipeline of new products. The market is segmented by bevacizumab, temozolomide and Gliadel Wafer (carmustine). Incident cases of GB are expected to increase by 23% during the forecast period. A detailed analysis of GB treatment market size and trends can be found at https://www.grandviewresearch.com/industry-analysis/glioblastoma-multiforme-treatment-gbm-market.
Problem
Brain and other nervous system cancer is the 10th leading cause of death for men and women. Globally, over 241,000 people die each year as a result of brain or nervous system cancer, with glioblastoma (GB) being the most common form of the disease. GB is a malignant brain tumor that develops from astrocytes, it is often aggressive and grows into surrounding normal brain tissues. The GB incidence is of 2-3 per 100,000 adults per year, and accounts for 52% of all primary brain tumors.
The most limiting aspects of this pathology are both the aggressiveness and high incidence of tumor recurrence after the first-line treatments , as well as difficulty in reaching the tumor and drug resistance. Signs and symptoms of GB are strictly related to the size and location of the tumor. The availability of only palliative treatments, as well as the risk of relapses, make GB the most malignant and lethal form of primary brain tumors.
Current Technology Limits
The standard therapy for glioblastoma is surgery, followed by radiation and chemotherapy. Despite the high invasiveness of this treatment, the survival rate is extremely low, with less than 5% of the patients surviving after 5 years. The site of the tumor, its aggressiveness and the likelihood of relapses make surgery alone ineffective. The efficacy of chemotherapy, on the other hand, is hampered by the high probability of insurgence of drug resistance, as well as the difficulty for many drugs to bypass the blood-brain barrier (BBB). Another issue related to current drugs is the narrow therapeutic window available to achieve sufficient efficacy with acceptable side effects.
Given the limitation of all current therapeutics (i.e. low specificity, several side effects, low bioavailability, difficulty to bypass the BBB etc.), development of novel approaches to treat GB remains a great unmet need.
Killer Application
The main application of our invention is the development of novel, more effective antitumor agents with drug-like properties and high therapeutic potential for the treatment of GB. The development of a post-surgery drug delivery system is an added value of the present invention, to circumvent the BBB and to prevent systemic drug clearance and/or chemical/enzymatic degradation, as well as to reduce systemic toxicity.
Our Technology and Solution
The present invention discloses small molecules 70-folds more effective in vitro than temozolomide on patient-derived tumoral cell lines, and with efficacy comparable to that of the new candidate bevacizumab, but with improved drug-like characteristics.
The cytotoxic activities of all New Chemical Entities (NCEs) have been evaluated in vitro via MTT assay against the two human cancer cell lines U87MG and RPMI 8226, representative of human glioblastoma multiforme (GBM) and multiple myeloma, respectively. Cell viability was assessed after 24 h of continuous treatment with NCEs at a single concentration and then the investigation extended only for effective compounds at different time points (24, 48, and 72 h) and different concentrations (1–60μM) by SRB assay. The ability of the most promising compounds to counteract cell motility and propagation was then proved by Boyden Chamber assay. The subsequent evaluation of NGF-induced neurite outgrowths performed on dorsal root ganglia (DRG) of 15-day-old embryonic Sprague-Dawley rats, demonstrated the absence of neurotoxic effect. Once the in vitro potential of selected compounds has been proved, the mechanism of action was preliminary investigated by evaluating their ability to inhibit proteasome complex by 7-Amido-4-Methylcoumarin fluorescent probe. The investigation of the mechanism is ongoing.
Advantages
Our invention will allow to develop novel anticancer agents with improved efficacy and bioavailability compared to current chemotherapeutics.
The disclosed compounds are 70-folds more active in vitro than temozolomide on GB and as effective as the new candidate bevacizumab, but with improved drug-like characteristics.
Since the patented compounds are small molecules, their development and scaled up production is easier than biotechnological drugs. The synthetic procedures were also developed with a greener approach decreasing the use of toxic solvents and hazardous reagents.
Roadmap
At the moment, our patented compounds are at the hit-stage and they present an efficacy comparable or superior to the current treatments.
We are currently defining the mechanism of action. To achive valuable drug candidates, further investments are needed:
TRL
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