søndag den 11. november 2012

Kinase inhibitors for diseases in the immune system

Protein kinases are used to transmit signals and to regulate the majority of cellular pathways.

Protein kinase inhibitors can be used as drugs for cancer and autoimmune diseases.

A search on "kinase inhibitors" in http://www.clinicaltrials.gov/ gave more than 2900 hits.

Pfizer has recently achieved a FDA approvel of a kinase inhibitor,Tofacitinib (Xeljanz). From the press release: XELJANZ is the first approved Rhematoid Arthritis treatment in a new class of medicines known as Janus kinase (JAK) inhibitors.

But are there any kinase inhibitors suited for treatment of ME??? And what shall we look for?

The article Chronic fatigue syndrome and subsequent risk of cancer among elderly US adults informs us that "CFS was associated with an increased risk of non-Hodgkin lymphom" and "Chronic immune activation or an infection associated with CFS may play a role in explaining the increased risk of NHL".

And the Rituximab study in Norway is giving us the hypothesis, that ME can be an autoimmune disease.

So, the hypothesis is that ME is a disease associated with "something wrong with B-cells".

Do we need a kinase inhibitor that controls B cells???  Could it be a treament for ME???

This is what I found about kinases and B cells:

Phosphatidylinositol 3-kinase (PI3K) activation regulates many steps in the development, activation and differentiation of both B- and T-cells. PI3Ks  are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer.

And from this article
Selective inhibitors of phosphoinositide 3-kinase delta: modulators of B-cell function with potential for treating autoimmune inflammatory diseases and B-cell malignancies
are the following quotes:
"The delta isoform of the p110 catalytic subunit (p110δ) of phosphoinositide 3-kinase is expressed primarily in hematopoietic cells and plays an essential role in B-cell development and function....
PI3Kδ also plays a critical role in the activation, proliferation, and tissue homing of self-reactive B cells that contribute to autoimmune diseases, in particular innate-like B-cell populations such as marginal zone (MZ) B cells and B-1 cells that have been strongly linked to autoimmunity....
Because PI3Kδ plays a major role in both B-cell-mediated autoimmune inflammation and B-cell malignancies, PI3Kδ inhibitors may represent a promising therapeutic approach for treating these diseases."

"Based on the findings described earlier, there are a number of reasons why PI3Kδ is a very promising target for the treatment of autoimmune inflammatory diseases, particularly those in which B cells play a major role. By blocking B-cell migration, adhesion, survival, activation, and proliferation, inhibition of p110δ activity would impair the ability of B cells to act as APCs that activate autoreactive T cells, prevent their activation, and reduces their secretion of autoantibodies and pro-inflammatory cytokines."

"As a proof-of-principle that PI3Kδ inhibitors can inhibit B cell-mediated autoimmune reactions in vivo, we showed that administering IC87114 to rats reduces autoantibody production in a model of collagen-induced arthritis (Durand et al.,2009)"

"PI3Kδ inhibitors such as IC87114 have now been shown to reduce the incidence and severity of autoimmune arthritis (Randis et al., ), asthma (Lee et al., ; Park et al., ), experimental autoimmune encephalomyelitis (Haylock-Jacobs et al., ), and SLE (Maxwell et al., ) in mouse models. Our current work suggests that oral administration of IC87114 opposes the progression of autoimmune diabetes in NOD mice. The ability of PI3Kδ inhibitors to reduce the severity of these inflammatory diseases may be due not only to their actions on innate-like B cells, but also to inhibitory effects on other immune cells that contribute to autoimmune disease (Fung-Leung, )."

"Providing a further rationale for the use of PI3Kδ inhibitors to treat autoimmune disease is the recent finding that enhanced PI3Kδ activity is associated with autoimmunity in humans (Suarez-Fueyo et al., ). PI3Kδ activity is significantly increased compared to normal individuals in T cells from ~70% of SLE patients, and this difference is greatest in patients with active disease."
"GS-1101 was the first selective inhibitor of PI3Kδ to enter clinical testing for various B-cell malignancies including CLL, non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), DLBCL, and MM. Remarkably, treatment with GS-1101 as a single agent provided durable remissions to a significant percentage of patients with CLL and certain subtypes of NHL (Sharman et al., ). Most of these patients had relapsed from multiple other treatment regimens yet responded to the p110δ inhibitor. GS-1101 also showed impressive efficacy when combined with standard-of-care agents (e.g., rituximab, bendamustine, and fludarabine) for indolent NHL (iNHL) and CLL. Currently GS-1101 has advanced to phase 3 clinical testing in CLL as a single agent or in combination with rituximab and bendamustine (clinical trial identifiers: NCT01569295, NCT01539291, and NCT01539512). "

...I wonder...can Rituixmab and GS-1101 be combined in treatment for ME???

"PI3Kδ activity is important for NK cell activation and function (Kim et al., ; Saudemont et al., ) and for induction of both the perforin-granzyme and death-receptor pathways of CTL-mediated tumor cell killing (Putz et al., )"

...ups...not so good..to use drugs, that suppresses NK cells activation, that already is poor in ME patients.

End of qoutes from the above article.

Another great article, but it is difficult to understand, but please do pass it on, if you know a ME researcher:
Akt and mTOR in B Cell Activation and Differentiation
They have a good point here, quote,: "Although antibody-mediated B cell depletion (anti-CD20; rituximab) often provides benefit for the treatment of B cell malignancies, PI3K/Btk-targeted small molecules might have some advantages. Such agents would be more rapidly reversible than long-lived antibodies upon cessation of treatment, allowing prompt resolution of adverse immunosuppressive effects. Small molecule orally active compounds might also be more convenient and less expensive to administer. It is also possible that PI3K/Btk inhibitors will be useful as adjuncts to rituximab, as suggested by preliminary reports of combination trials in non-Hodgkin’s lymphoma (Fruman and Rommel, ; Winer et al., )."

And the last article I liked, is this one:
PI3K signalling in B- and T-lymphocytes: new developments and therapeutic advances
"Genetic and pharmacological experiments have shown that PI3K activation regulates many steps in the development, activation and differentiation of both B- and T-cells. These findings have prompted the development of PI3K inhibitors for the treatment of autoimmunity and inflammatory diseases. PI3K activation, however, has both positive and negative roles in immune system activation. Consequently, although PI3K suppression can attenuate immune responses it can also enhance inflammation, disrupt peripheral tolerance and promote autoimmunity. An exciting discovery is that a selective inhibitor of the p110δ catalytic isoform of PI3K, CAL-101, achieves impressive clinical efficacy in certain B-cell malignancies. A model is emerging in which p110δ inhibition disrupts signals from the lymphoid microenvironment, leading to release of leukaemia and lymphoma cells from their protective niche. These encouraging findings have given further momentum to PI3K drug development efforts in both cancer and immune diseases."

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