Another cure from cancer. Again! (Post No 11)

Yes, but today we have 3 magic cures! Two new usual “targeted” tyrosine kinase inhibitors: Ponatinib (from wiki:

The primary target for ponatinib is BCR-ABL, an abnormal tyrosine kinase that is the hallmark of CML and Ph+ ALL. CML is characterized by an excessive and unregulated production of white blood cells by the bone marrow due to a genetic abnormality that produces the BCR-ABL protein. After a chronic phase of production of too many white blood cells, CML typically evolves to more aggressive phases such as accelerated or blast crisis. Ph+ ALL is a subtype of acute lymphoblastic leukemia that carries the Ph+ chromosome that produces BCR-ABL. It has a more aggressive course than CML and is often treated with a combination of chemotherapy and tyrosine kinase inhibitors. Because both of these diseases express the BCR-ABL protein, this would render them potentially susceptible to treatment with ponatinib. BCR-ABL is detected in 95% of patients with CML. Patients with CML currently receive front line therapies nilotinib and/or dasatinib though 22-33% of patients discontinue therapy by two years due to adverse events, treatment failure and other causes.)

and Cabozantinib:

Ariad Pharmaceuticals Inc. (NASDAQ:ARIA) began submission of a rolling NDA to FDA for ponatinib to treat resistant or intolerant chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The company, which requested Priority Review for the application, is seeking accelerated approval for ponatinib based largely on data from the pivotal Phase II PACE trial. In June, Ariad reported data showing that 54% of chronic phase CML patients who were resistant or intolerant to tyrosine kinase inhibitor therapy, including 70% of patients with the T315I variant of BCR-ABL tyrosine kinase, achieved a major cytogenetic response. Ariad's proposed indication includes, but is not limited to, patients with the T315I mutation.

…

Exelixis, Inc. (EXEL) today announced that the U.S. Food and Drug Administration (FDA) has accepted for filing the New Drug Application (NDA) for cabozantinib as a treatment for patients with progressive, unresectable, locally advanced, or metastatic medullary thyroid cancer (MTC). The FDA also granted priority review designation to the NDA for cabozantinib.

Cabozantinib is a potent inhibitor of MET, VEGFR2 and RET. RET is a receptor tyrosine kinase that is frequently activated by point mutation in medullary thyroid carcinomas. The therapeutic role of cabozantinib is currently being investigated across several tumor types. MET is upregulated in many tumor types, thus facilitating tumor cell escape by promoting the formation of more aggressive phenotypes, resulting in metastasis. MET-driven metastasis may be further stimulated by hypoxic conditions in the tumor environment, which are often exacerbated by selective VEGF-pathway inhibitors. In preclinical studies, cabozantinib has shown powerful tumoricidal, antimetastatic and antiangiogenic effects, including:

•Extensive apoptosis of malignant cells

•Decreased tumor invasiveness and metastasis

•Decreased tumor and endothelial cell proliferation

•Blockade of metastatic bone lesion progression

•Disruption of tumor vasculature

But the third approach is not usual targeted bogus – it looks like really rocket science which is really worth of citation!

The drug is called SNS01-T:

Senesco’s therapeutic candidate, SNS01-T comprises three components: a DNA plasmid, a small inhibitory RNA (siRNA) and polyethylenimine (PEI). The DNA plasmid expresses eIF5AK50R (human eIF5A containing a lysine to arginine substitution at amino acid position 50) that up-regulates the apoptotic pathways within cancer cells. By RNA inhibition (RNAi), the siRNA down-regulates the production of hypusine eIF5A and by this mechanism suppresses anti-apoptotic proteins, NF-kB, ICAM and pro-inflammatory cytokines, which are proliferation factors for multiple myeloma. PEI is a cationic polymer that promotes self-assembly of nanoparticles with demonstrated enhanced delivery to tissues and protection from degradation in the blood stream.

SNS01-T is the subject of an open IND and an on-going study in multiple myeloma.

Preclinical studies have shown that SNS01-T is able to promote the elimination of cancer cells through multiple validated mechanisms including:

i. Down-regulating NFkB and anti-apoptotic proteins

ii. Up-regulating p53 and pro-apoptotic proteins

iii. Blocking the IL-6 paracrine growth signal among cells in the tumor environment

The DNA plasmid for eIF5AK50R is under the control of the B29 promoter and enhancer, which has been shown to restrict expression to B-cells (Hermanson et al, 1989; Hermanson et al, 1988; Malone et al, 2006). The mode of action of SNS01-T employs an eIF5A-specific siRNA to reduce the pool of hypusinated eIF5A in myeloma cells, while simultaneously producing eIF5AK50R that mimics the lysine protein, but cannot be hypusinated. This approach promotes apoptosis of multiple myeloma cells, while simultaneously depleting cellular levels of hypusinated eIF5A, which normally protects the cells from apoptosis. SNS01-T reduces tumor burden in murine myeloma models without damaging normal tissues.

I am impressed, aren't you? Not yet? Well, the approach can be promising for treatment of both mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL)!

Senesco Technologies, Inc. (“Senesco” or the “Company”) (NYSE MKT: SNT) reported today that it was informed on July 26th that the U.S. Food and Drug Administration (FDA) has granted orphan-drug designation for the company’s lead drug candidate SNS01-T for treatment of both mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL).

Let's hope that all these 3 drugs will help somehow to fight cancers!