Research & Development Focus Areas

Cancer Adjuvant Therapies

Curcumin as tyrosine kinase inhibitor in cancer treatment

Curcumin is a natural substance known for ages, exhibiting a multidirectional effect in cancer prevention and adjuvant cancer therapies. The great advantage of using nutraceuticals of vegetable origin in comparison to popular cytostatic drugs is the minimized side effect and reduced toxicity. The targets in oncological therapy are, among others, tyrosine kinases, important mediators of signaling pathways whose impaired expression is observed in many types of cancer. Unfortunately, the hydrophobic nature of the curcumin molecule often limits its bioavailability, which is why many studies focus on the chemical modification of this compound. Current research is aimed at modifying structures that improve the pharmacokinetic parameters of curcumin, e.g. the formation of nanoparticles, complexes with metals or the synthesis of curcumin derivatives with functional substituents that allow tumor targeting.

Our research

In combinatorial therapies with the kinase inhibitors, we achieved very promising and unambiguous in vitro results and are currently moving to the mice model in order to clearly demonstrate the possibility of using NOMICU® L-100 as an enhancer (to lower down the dose of hepatotoxic and nephrotoxic effects of kinase inhibitors used in chemotherapies).

Inflammation

Anti-inflammatory properties of curcumin

Research has shown curcumin to be a highly pleiotropic molecule capable of interacting with numerous molecular targets involved in inflammation. Based on early cell culture and animal research, clinical trials indicate curcumin may have potential as a therapeutic agent in diseases such as inflammatory bowel disease, pancreatitis, arthritis, and chronic anterior uveitis, as well as certain types of cancer. Because of curcumin’s rapid plasma clearance and conjugation, its therapeutic usefulness has been somewhat limited, leading researchers to investigate the benefits of complexing curcumin with other substances to increase systemic bioavailability. Numerous in-progress clinical trials should provide an even deeper understanding of the mechanisms and therapeutic potential of curcumin.

Rare Diseases

Ondine’s curse – CCHS – Congenital Central Hypoventilation Syndrome

Ondine’s curse—more appropriately known as congenital central hypoventilation syndrome, or CCHS—is a rare and severe form of sleep apnea in which an individual completely stops breathing when falling asleep. It is always congenital, meaning that it is present from birth. There is also an acquired form of central hypoventilation syndrome that can result from brain or spinal injury or neurodegenerative diseases. Central sleep apnea is characterized by the brainstem failing to prompt normal breathing. This seems to be due to a decreased responsiveness to high levels of carbon dioxide and low oxygen levels within the blood. This becomes especially dangerous during sleep. Ondine’s curse is named after a mythical tale in which a heartbroken water nymph curses her unfaithful husband to stop breathing should he ever fall asleep. In medical terms, Ondine’s curse represents an extreme form of sleep apnea.

Causes

Ondine’s curse affects about one in 30 million people, which means only several hundred people have it in the world. As such, it is considered to be an extremely rare condition. A genetic mutation appears to be the underlying cause. It is thought to occur when the brain fails to prompt breathing, as may also be seen in central sleep apnea.

When the condition is present from birth, Ondine’s curse may be associated with difficulty swallowing, intestinal problems called Hirschsprung’s disease, or tumors called neuroblastoma. Both the congenital and acquired forms can cause symptoms related to low oxygen during sleep, including shallow breathing while sleeping, cyanosis in the fingers or toes, seizures, heart abnormalities, and cognitive difficulties. The congenital form almost always presents in the newborn period, while the non-congenital form happens later in life (for example, after spinal cord surgery or with brainstem tumors or strokes). CCHS can also be associated with other disorders, including tumors of the nervous system (neuroblastomas, ganglioneuromas, ganglioneuroblastomas), eye abnormalities, and characteristic facial features (short, wide, flattened face), whereas the acquired type is not.children after having a child with CCHS are encouraged to seek genetic counseling.

Though the condition usually occurs sporadically, there may be a genetic tendency that runs in families. Relatives may have a milder form of dysfunction that affects the autonomic nervous system. In 2003, the PHOX2B gene was identified as the disease-defining gene for CCHS, providing pathologists the means to definitively diagnose this disease and provide early treatment.

Symptoms

Most affected individuals have an onset shortly after birth, though cases have also been diagnosed in utero. Symptoms may appear in milder cases with the use of anesthesia or sedatives.

People with CCHS take shallow breaths (hypoventilate), especially during sleep, resulting in a shortage of oxygen and a buildup of carbon dioxide in the blood.

Reduced and shallow breathing is most apparent in non-REM sleep but can even occur during REM sleep or when fully awake, albeit to a lesser degree.

Other symptoms include acid reflux and poor upper gastrointestinal motility, which manifests with nausea, pain, dysphagia (difficulty swallowing), and vomiting.

Treatment

Treatment involves the use of a mechanical ventilator connected to a tracheostomy tube in front of the throat. The ventilator ensures normal breathing whenever the person goes to sleep, even during naps. If this were not used, someone with CCHS could die anytime they fall asleep.

Reflux is often treated with medications, while poor upper gastrointestinal motility may often be managed with diet and altered eating habits.

Due to the nature of the treatment, families of those afflicted often become adept at managing the equipment required to maintain normal breathing. It may initially seem intimidating, but help within the hospital setting allows a smooth transition to treatment at home. Guidance from respiratory therapists, including possible at-home assistance, can ease this adjustment.

Our research

In a research collaboration with the our French partners from Imagine Institute of Genetic Diseases https://www.institutimagine.org/en we investigate a partial recovery of transcriptional activity of the selected PhoX2b mutants by the inhibition of Hsp90 protein with NOMICU® L-100 – our novel formulation of highly bioavailable curcumin. The main aim of the project is to investigate the role of the Hsp90 protein in the degradation of misfolded mutants of the PhoX2b protein using NOMICU® L-100 as a non-toxic inhibitor of Hsp90. By constructing an expression library of selected PHOX2B mutants and developing a luciferase assay-based reporter system, we will be able to study the effective dose dependent inhibition of Hsp90 on partial recovery of the transcriptional activity of PhoX2b protein. Given that targeting the proteasomal degradation of Phox2b protein aggregates is highly likely modulated by the Hsp90 heat shock protein, we believe that Hsp90 might be considered as therapeutical target in CCHS patients.