Signpath Pharma is a clinical stage biotechnology company founded in 2006.
Many diseases and other pathological states are caused or made worse by a breakdown in signals between cells, between activities inside cells, or between organs and systems.
Signpath Pharma is focused on deciphering the mechanism behind these signals, and using this understanding to develop novel therapies.
Currently, Signpath is developing products to treat cancer, neurologic disorders and mitigate drug-induced cardiac arrhythmia.
Synthesized Curcumin – LipoCurc
Curcumin-like compounds are found in a genus of root vegetables that includes turmeric and ginger. Signpath is currently in clinical development of a synthetic curcumin compound used to treat cancer. Curcumin is very poorly absorbed so only limited amounts are bioavailable when used as a drug product. To circumvent this Signpath’s has developed a proprietary liposomal formulation (LipoCurcTM) which achieves high bioavailability and pharmacologically effective concentrations when injected directly into the blood. In in vitro experiments we have demonstrated that in low doses, curcumin is anti-inflammatory; it reduces the production of cytokines including Interleukins (IL), Tumor Necrosis Factor (TNF) and Interferon, among others. In high doses curcumin promotes cell death (apoptosis) especially in tumors. Signpath has completed Phase 1a and Phase 1b safety trials in human patients. These clinical trials showed that LipoCurcTM is well tolerated at clinically relevant doses. We are preparing to initiate Phase 2 trials with LipoCurcTM in glioblastoma patients who have failed first line therapy.
Mitigation of Cardiac Arrhythmia Side Effects:
Signpath has identified and is developing compounds that alleviate the cardiac arrhythmia that is a common side effect of over 180 approved drugs. These drugs slow the heart-beat by altering the polarization and repolarization of heart muscle. This is demonstrated on the electrocardiogram by an abnormality called QT-prolongation. In QT prolonging drugs, the interval between the Q wave and the T wave is dangerously extended; which can lead to heart failure.
In vivo testing of Signpath’s lead compound, SP4040, has shown that administration of SP4040 concomitantly with a QT-prolonging drug eliminates the dangerous QT-prolongation side effect induced by the second drug. This mitigation of QT-prolongation has been observed in conjunction with various classes of compounds, including anti-cancer agents, antibiotics, antipsychotics, antihistamines and other drugs.
Signpath expects to initiate human clinical trials with SP4040 in 2017.
The Science Behind the Drugs:
Both of the Company’s lead compounds (liposomal curcumin and SPP4040) act through important biochemical signaling pathways centered around Ceramides, and their interactions with Sphingosine 1-phosphate-S1P (S1P);
Ceramide is one compound in a family comprised of 50 distinct molecular species. Ceramide is an N-acylsphingosine consisting of a fatty acid bound to the amino group of the sphingoid base, sphingosine. Ceramides can contain monounsaturated or saturated fatty acids of various lengths from 2 to 28 carbon atoms, and the fatty acid chain length profoundly alters ceramide’s biophysical properties. As an agent of cell signaling, ceramide activates a variety of protein kinases. Differential activation of these proteins determines the nature of the signal and its effect on the cell. Generally, in cancer cells ceramides favor anti-proliferative and cell death pathways (such as senescence and apoptosis).
Sphingosine 1-phosphate-S1P (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and −2 (SPHK1 and SPHK2). Elevated SPHK1 has been found in numerous cancer types and been shown to contribute to chemotherapeutic resistance and malignancy.
It exerts opposite roles in cells compared to ceramide by mediating cell survival and proliferation. S1P is bioactive at concentrations two to three orders of magnitude lower than those of ceramide, consistent with their relative cellular concentrations. Fractional conversion of ceramide to Sph or S1P can have profound cellular effects.
Controlling the balance between Ceramide & sphingosine-1 Phosphate (S1P)
Sphingosine 1-phosphate-S1P (S1P) is a potent bioactive sphingolipid metabolite produced by sphingosine kinases-1 and −2 (SPHK1 and SPHK2). Elevated SPHK1 in cancers contributes to drug resistance and malignancy progression.
It exerts opposite roles in tumor cells compared to ceramide by mediating cell survival and proliferation. S1P is bioactive at concentrations two to three orders of magnitude lower than those of ceramide, consistent with their relative cellular concentrations. Therefore, fractional conversion of ceramide to Sphingosine or S1P can have profound cellular effects.
Since ceramides favor anti-proliferative and cell death pathways (such as senescence and apoptosis) and in contrast, S1P stimulates cell proliferation and survival pathways, they constitute important signaling molecules regulating cell fate decisions. Influencing the the ratio of ceramide in relation to S1P leads to a seesaw of cell survival vs cell death through a variety of signaling pathways impinging on the processes of cell proliferation, apoptosis, autophagy and senescence.
One of the therapeutic implications of the Ceramide/S1P Balance include increasing Apoptosis in tumors via raising Ceramide relative to S1P.
For more information and details on our science, please refer to our patents and publications listing HERE.