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Post by itellthefuture777 on Jul 30, 2017 20:05:14 GMT -5
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Post by itellthefuture777 on Jul 30, 2017 20:07:06 GMT -5
Magnificent find! I almost spilt my plate of food over when I read the description of the abstract. What you found pertains to MannKind's IRE-1α inhibitors patents, and our friend John B. Patterson is an inventor on one of them (they have several via continuations). It pertains to XBP-1 endoribonuclease inhibition like in the patent below. First I am gonna paste the abstract you found. Excellent find. • MannKind Abstract May 18, 2017 PRECLINICAL COMBINATION OF A NOVEL IRE1 RNASE INHIBITOR MKC-8866 AND TYROSINE KINASE INHIBITION ACTS SYNERGISTIC IN ACUTE LYMPHOBLASTIC LEUKEMIA. Author(s): Margherita Vieri , Azam Salimi , John B. Patterson , Afshin Samali , Eric Chevet , Tim H. Brümmendorf , Iris Appelmann , Behzad Kharabi Abstract: E819 Type: Eposter Presentation Background
The role of the Unfolded Protein Response (UPR) in BCR-ABL1+ Acute Lymphoblastic Leukemia (ALL) has been extensively studied, proving the IRE1-XBP1 branch to be required for leukemic cell survival. However, a therapeutic strategy involving UPR inhibition that possesses translational impact is yet to be identified. Aims
In this study we aim to identify a potential synergistic effect of simultaneous pharmacological inhibition of IRE1 and BCR-ABL1 in BCR-ABL1+ ALL. Methods
To study the link between IRE1-XBP1 axis of UPR and BCR-ABL1 we utilized both pharmacological and genetic approaches. 1) We tested the effect on proliferation and viability of pharmacological IRE1 inhibition (using MKC-8866) alone and in combination with Tyrosine Kinase Inhibitors (TKI, using Imatinib or Nilotinib) on BCR-ABL1+ human ALL cell lines, SUP-B15 and TOM-1. The cell lines were also co-cultured with immortalized tertMSCs to test the chemo-protective effect of bone marrow stromal cells (BMSCs) on leukemia cells. 2) We tested whether genetic knock-down of XBP1 could sensitize cells towards the effect of Imatinib and Nilotinib. To this end, primary murine pre-B cells from conditional XBP1fl/+ mice were transduced with BCR-ABL1 construct, and with either inducible cre or empty vector. Results
IRE1 inhibitor MKC-8866 (MKC) in combination with either Imatinib (IM) or Nilotinib (NL) showed enhanced capacity to arrest proliferation and to induce cell death in BCR-ABL1+ ALL cell lines compared to single treatments, after 3 days incubation (Viable SUP-B15: MKC 30µM 94.9%±0.1, IM 10µM 78.4±0.4, Combination 17.0±1.4; MKC 30µM 94.1±0.07, NL 5µM 64.2±0.6, Combination 20.0±0.8. TOM-1: MKC 30µM 85.0±0.9, IM 10µM 89.9±0.4, Combination 17.6±0.07; MKC 30µM 94.6±0.1, NL 5µM 71.0±0.9, Combination 30.6±3.6). Using Bliss independence formula, we confirmed a striking synergistic effect. Successively, to exclude any possible off-target effect at the basis of the observed synergism, we used a genetic approach to block IRE1-XBP1 signaling in vitro. B-cell precursors from Xbp1fl/+ mice, instead of Xbp1fl/fl, were used in order to warrant a basal signal of XBP1, as present during pharmacological inhibition. After transductions with BCR-ABL1, and either cre or the empty vector, we could observe that heterozygous deletion of Xbp1, induced by 4OHT, significantly increased TKI-induced cell death, after 3 days incubation (4OHT 1µM: 47.5%±13.0, IM 1µM: 70.8±1.7, IM+4OHT: 18.3±2.7, NL 0.5µM: 65.2±0.3, 4OHT+ NL: 6.87±1.2). Finally, we showed whether the tested drugs combinations were still effective in presence of BMSCs. It´s know that BMSCs are a critical component to escape TKI-induced cell death in Ph+ leukemia and that IRE1-XBP1 is responsible for chemoresistance in many different cancer types, although this role has never been confirmed in BCR-ABL1+ cells. To shed light on this aspect we co-cultured either SUP-B15 or TOM-1 cells with tertMSCs, and while the stroma was capable to block Nilotinib-induced cell death, after 5 days incubation (in SUP-B15, NL 5µM in standard culture 28.7%±1.9, NL 5µM in co-culture 74.9±0.1; in TOM-1, 29.1±2.8 vs 78.7±0.4), this protective activity was partially abrogated upon treatment with IRE1 inhibitor. On the other hand, MSCs were not able to reverse IM effect on cell viability. Conclusion
Overall, our data demonstrate that simultaneous inhibition of BCR-ABL1 and IRE1 branch of UPR exerts a potent effect in vitro, by acting synergistically on BCR-ABL+ ALL cells. This provides basis for a pre-clinical application of a combined targeted therapy. Session topic: 1. Acute lymphoblastic leukemia - Biology
Keyword(s): Tyrosine kinase inhibitor, BCR-ABL, Acute lymphoblastic leukemia • MannKind Patent with John B. Patterson IRE-1α inhibitors Read more: mnkd.proboards.com/thread/8210/#ixzz4oMos5tq5 |
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Post by mango on Jul 30, 2017 20:57:08 GMT -5
Those are just the Sponsors of the European Hematology Association
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Post by itellthefuture777 on Jul 30, 2017 21:28:36 GMT -5
Novartis isn't "just" a sponsor...the two drugs used with Mannkind's are Novartis's..I mean to say...sure they contributed to whom ever to pay for the study along with others but...the 2 drugs are also...Novartis's drugs in combination with Mannkind's drug..then.. I add the.. hmmmm?
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Post by itellthefuture777 on Jul 30, 2017 21:32:30 GMT -5
I also see Roche there as well..hmmm?
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Post by itellthefuture777 on Jul 30, 2017 21:33:07 GMT -5
Visit the link to see what I am saying...
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Post by peppy on Jul 31, 2017 3:30:50 GMT -5
I opened the study link. Acute Lymphoblastic Leukemia (ALL)
I believe Mango is correct, roche, Novartis, etc listed as sponsers. No one reads these studies better than Mango. He CAN find the needle in the haystack.
On the Mannkind Note: Mannkind does have a far share of patents in the leukemia area. The Lymph is this case, as this is lymphoblastic.
That's my take on this one.
added: Use the article named for the thread. An article post is put under articles.
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Post by itellthefuture777 on Jul 31, 2017 10:24:00 GMT -5
Yes they are..So..Novartis drug in combination with Mannkinds drug...
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Post by peppy on Jul 31, 2017 10:33:04 GMT -5
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Post by mango on Jul 31, 2017 12:47:05 GMT -5
MannKind has patents for both IRE-1a inhibitors and tyrosine kinase inhibitors.
You can click on the main homepage of the website and all those sponsors are listed. They're just the major sponsors of the European Hematology Association.
Used in combo doesn't mean they are collaborating with anyone. Some drugs are already first line therapy and patients become drug resistant. Tolero talks about this a lot within their presentations and posters too. I don't see any indication of collaboration just see this highlighting MannKind's compound.
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Post by itellthefuture777 on Jul 31, 2017 14:39:27 GMT -5
The preclinical study..which were positive in summary...in combination with Novartis's drugs..either one of them...with Mannkinds drug...as now reported...doesn't indicate the past non collaboration...but a possible future that looks bright for the patient
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