CLL-Forschung + Ergebnisse mit Ibrutinib

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Stintino
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Stintino » 26.06.2013, 14:36

Hallo zusammen,

hier noch mal ein Beitrag zur CLL-Forschung, zitiert aus "Hermatology Times" vom 17. Mai 2013 unter der Überschrift "Combo can override resistance in CLL"

Grüße, Stintino


A BH3 mimetic and a BCL2 inhibitor, when administered in combination, can induce apoptosis in resistant chronic lymphocytic leukemia (CLL) cells, a preclinical study suggests.

Though BCL2 inhibitors have demonstrated efficacy against CLL, leukemia cells residing in lymph nodes and the bone marrow have proved resistant to these drugs.

But now, researchers have found that by introducing the BH3 mimetic gossypol, they can sensitize CLL cells to the BCL2 inhibitor ABT-737.

The group described this research in a letter published in Leukemia (which is only available to subscribers).

“We have been studying the mechanism in the cancer cells that causes the resistance to treatment, and that, in turn, led us to find drugs that target the resistance,” said study author Alan Eastman, PhD, of the Geisel School of Medicine at Dartmouth College in Hanover, New Hampshire.

Dr Eastman and his colleagues knew the CLL cells’ resistance is due to the upregulation of BCL2 proteins such as BCLXL, MCL1, and BFL1. And neither MCL1 nor BFL1 is inhibited by ABT-737.

But the BH3-only protein NOXA does inhibit MCL1 and BFL1, as well as BCLXL. So the researchers hypothesized that a compound that induces NOXA—such as gossypol—might inhibit the 3 proteins and overcome CLL cells’ resistance to ABT-737.

To test that, the investigators introduced both drugs, first alone and then in combination, to samples from CLL patients.

The team incubated CLL cells with up to 10 μM of ABT-737 alone and found the cells “highly sensitive” to the drug. Apoptosis occurred within 6 hours, and most cells underwent apoptosis with doses between 10 nM and 100 nM.

Gossypol alone (given at 5 μM to 20 μM) had only a minimal apoptotic impact within the same time frame, although the drug did induce NOXA.

However, when the drugs were administered together, gossypol sensitized the cells to ABT-737. Most of the cells underwent apoptosis with doses between 1 nM and 10 nM.

To mimic the protective microenvironment seen in patients and promote resistance to ABT-737, the researchers incubated CLL cells with fibroblasts expressing CD154. After 24 hours, there was a marked increase in BCLXL and a variable increase in BFL1 but no significant increase in MCL1.

In these conditions, most cells required 1 μM to 10 μM of ABT-737 to induce apoptosis. But gossypol resensitized the cells to ABT-737 in a concentration-dependent manner. Apoptosis occurred with doses of ABT-737 between 10 nM and 100 nM.

Dr Eastman and his colleagues also wanted to determine if gossypol and ABT-737 had similar effects on normal lymphocytes and platelets. Experiments revealed that lymphocytes were not sensitive to the drugs, either alone or in combination.

Platelets, on the other hand, were sensitive to ABT-737 at a dose of 10 μM. But the addition of gossypol did not further sensitize platelets to ABT-737.

Taking these results together, the researchers said it seems plausible that ABT-737 and gossypol can kill resistant CLL cells within the stromal niche and improve clinical outcomes. And since both drugs have been tested in humans, a clinical trial of the combination is feasible.

“Both drugs have been given to patients, but never in combination, because no one had the mechanistic rationale for doing that,” Dr Eastman said. “Now we have what we think is the most promising drug combination so far for the treatment of CLL.”

Stintino
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Stintino » 06.04.2013, 14:44

Hallo zusammen,

hier noch mal eine News zu neuen Forschungsansätze, zitiert aus "CLL Global Research Foundation", April 2013.
Grüße, Stintino
_________________________________________________

Preparing for Future Clinical Trials

Dr. Michael Hallek and his team at the University of Cologne used blood samples from CLL patients to study certain drug combinations in the laboratory. They were hoping to gain clues as to the mechanism of action of the tested drugs which would allow the design of meaningful drug combinations. The group looked specifically at drug induced changes in cell survival and intracellular signaling.

Dr. Michael Hallek (University of Cologne)
Part of the work looked at mAb37.1, a novel monoclonal antibody directed against CD37, an antigen expressed on the surface of CLL cells similar to CD20, the target of rituximab. According to Hallek, mAb37.1 induced cell death and depleted CLL cells from the blood much more efficiently than rituximab. Based on these results, the group combined mAb37.1 with chemotherapeutic agents fludarabine and chlorambucil. These combination studies in the laboratory continue, but the compound mAb37.1 has moved into a Phase I clinical trial conducted by the German CLL Study Group.

Another component of Dr. Hallek's project is to look at kinase inhibitors that could be used as CLL therapy. They are in the process of developing a tool for determining the effects of certain tyrosine kinase inhibitors that have been effective in chronic myelogenous leukemia (CML). These inhibitors target enzymes that are also involved in CLL cell microenvironment interactions and cellular survival functions.

The group is also screening laboratory-derived versions of colchicine. Colchicine is found in the seeds of the late blooming, highly-toxic flower, meadow saffron. It is used to treat gout. The drug has been shown to inhibit cell growth and division which makes it a good prospect for cancer therapy; however its toxicity prevents its use as cancer therapy. Dr. Hallek's colleagues are hoping to develop a modified version that is less toxic.

As you can tell, Dr. Hallek's project covers a variety of topics in new drug development. CLL Global has provided over $225,000 in funding over the last three years to support this work. The research group has in turn leveraged the CLL Global funding into an additional $950,000 from two German organizations, showing a true ripple effect of CLL Global's support.

WR
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von WR » 28.03.2013, 09:27

a humanized monoclonal antibody that targets and directly kills chronic lymphocytic leukaemia (CLL) cells.
http://www.medicalnewstoday.com/releases/258193.php
"We plan to initiate clinical trials using this humanized anti-CD44 monoclonal antibody in the not-too-distant future."


receiving bioengineered T cells
http://www.medicalnewstoday.com/releases/258218.php
The Penn team reported on early successful results of a trial using this cell therapy in three adult chronic lymphocytic leukemia (CLL) patients in August of 2011. Two of those patients remain in remission more than 2½ years following their treatment,


Der Status aller klinischen Versuche jederzeit abrufbar unter
http://www.clinicaltrials.gov/ct2/resul ... rch=Search

Gast

CLL-Forschung: Tenovin

Beitrag von Gast » 07.03.2013, 11:01

Researchers at the University of Dundee have found a new way to kill cancer cells in people with one of the most common forms of leukaemia.
The team looked at chronic lymphocytic leukaemia (CLL) and its reaction to treatment with the drug Tenovin.

Tenovin was found to kill the cancer in Leukaemia patients without affecting the level of a tumour-suppressing protein.
It is thought it could lead to improved treatments in future.

Normally, Tenovin affects cancer cells by increasing levels of the "guardian angel" protein p53 within cells, which plays a crucial role in controlling cell mutations.
However, the team found that when treated with the drug, the CLL cells died but without showing a change in p53 levels.

The scientists then discovered that in leukaemic cells, Tenovin is able to interfere with the process of "self-digestion" that leukaemic cells use to protect themselves during periods of stress.

The study was led by Dr Sudhir Tauro from the Dundee Cancer Centre at Dundee University. Based on these findings, we can...begin to develop safer anti-leukaemic drugs for CLL” Dr Sudhir Tauro University of Dundee

He said: "This process, called autophagy, is important to the survival of all cells.
"It is noteworthy that while it has the important effect of disrupting this process in CLL cells, Tenovin did not affect normal blood-forming cells.

Current anti-leukaemia drugs often cause toxicity-related problems, particularly in older patients where treatment can affect a normal blood count.
They also tend to become less effective when used repeatedly.

The study has been funded by the charity Tenovus, which also supported the original development of Tenovin.

Prof Peter Howie, from Tenovus Scotland, said: "The aim of Tenovus Scotland-Tayside is to support medical research in Tayside which will ultimately lead to the benefit of patients.

"Tenovus in Tayside is delighted to see that its investment in the development of Tenovin is being taken forward by Dr Sudhir Tauro's exciting work in leukaemia."

Zitiert aus http://www.bbc.co.uk 04.03.2013

Micha67
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Micha67 » 28.11.2012, 19:54

Hallo zusammen,

in Köln ist auch eine Studie mit Ibrutinib in Vorbereitung. Sie soll Anfang nächsten Jahres starten. Der genaue Termin steht noch nicht fest, weil das Protokoll noch bei der deutschen Ethikkommission liegt. Erst nachdem es dort genehmigt ist, kann die Studie starten. So wie ich das von den Ärzten gehört habe, soll FCR mit Ibrutinib komibiniert werden.

Viele Grüße aus der KMT Station der Uniklinik Köln

Michael

Gast

Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Gast » 15.11.2012, 13:50

Hier noch mal ein ganz interessanter Beitrag aus der Forschung, zitiert aus "CLL Global Research Foundation, CLL TIDBITS" vom November 2012
Grüße, Stintino
___________________________________________________

Project Update: Overcoming CLL Drug Resistance

Drug resistance has been a major challenge in the clinical treatment of CLL patients. In the past, researchers were perplexed that a drug would work well in the laboratory but was not as effective when given to patients. It is now known that the microenvironment (the tissue environment where the CLL cells reside in the body, i.e. lymph nodes, bone marrow and spleen) provides protection and resistance to drugs.

Previously, CLL cells were isolated from patient blood samples for laboratory testing. Testing isolated CLL cells did not subject the cells to the factors in the microenvironment. This meant that the cells in the lab were not responding to drugs in the same way as cells in the body. Now CLL cells are co-cultured with stromal cells to mimic the microenvironment. Stromal cells communicate with and support CLL cells.
Dr. Peng Huang

For his Alliance project, Dr. Peng Huang (MD Anderson Cancer Center) has been conducting laboratory studies to better understand the interactions between the CLL and stromal cells. Dr. Huang has discovered an important pathway by which stromal cells help the CLL cells survive and resist the cytotoxic effects of drugs. He has also developed strategies which overcome the drug resistance caused by stromal protection.

As a cell produces energy through a process called oxidative metabolism, it releases molecules such as ROS that can be harmful to the cell. Glutathione is a major cellular antioxidant responsible for removing ROS, detoxifying other harmful molecules, and promoting drug resistance.

CLL cells have limited ability to produce glutathione due to low expression of a critical molecule. However, stromal cells feed CLL cells with a chemical needed to make glutathione. This helps CLL cells to survive under ROS stress and resist drug treatment.


Lab studies indicate that abolishing glutathione protection leads to the enhancement of a drug's toxic effect on CLL cells. Dr. Huang has tested two compounds, PEITC and SSZ. Both are successful in removing the drug resistant shield provided to CLL cells by the stromal cells.

PEITC (phenethyl isothiocyanate) is a molecule found in cruciferous vegetables like broccoli and Brussels sprouts. It reduces glutathione in CLL cells and prevents removal of the drug molecules from the cell. SSZ (sulfasalazine) is currently used for rheumatoid arthritis and inflammatory bowel disease. It was recently found that SSZ can block stromal cells from providing the chemical needed for CLL cells to produce glutathione.

Cruciferous vegetables like cabbage, broccoli and cauliflower have shown anticancer activity against many cancers. Image provided by lancastria.net

Dr. Huang also tested combinations of PEITC with standard chemotherapeutic agents. There was a notable increase in the effectiveness of the chemotherapy, even in the presence of stromal cells. As an added benefit, PEITC is effective in killing CLL cells with chromosome 17p deletion. This is important because cells with 17p deletion are often resistant to conventional therapeutic agents.

A clinical protocol has been developed to test PEITC in humans. The next step is to submit the protocol for FDA approval. While Dr. Huang has been studying PEITC for several years, the work done through his Alliance project has helped him to provide needed data and documentation for planning future clinical trials. SSZ has not been as extensively studied in CLL, but initial results are promising and the compound will be further investigated.

Stintino
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Stintino » 15.10.2012, 13:46

...diese Seite gibt einen Überblick über alle international laufenden Studien zur CLL:
http://clinicaltrials.gov/ct2/results?t ... rch=Search

Zusätzlich zu den schon erwähnten Studien mit Ibrutinib in Kombination mit Bendamustin und Rituximab gibt es in den USA also auch eine offene, noch rekrutierende Studie mit Ibrutinib als Monotherapie (Ohio State University, Comprehensive Cancer Center)

Grüße, Stintino

Enkidu
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Enkidu » 15.10.2012, 12:12

Ja, klingt vielversprchend.
In einer münchner Universitäts-Klinik wird die Studie angeboten. Allerdings nur in der Kombination Bendamustin zusammen mit Rituximab und Ibrutinib. Eine Vortherapie mit Bendamustin muss dabei mindestens 2 Jahre zurückliegen.
Gibt es also auch Sttudien in anderen Kombinationen, und wo?
Danke im Voraus für Antworten.

Besten Gruß
Enkidu

Stintino
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Stintino » 11.10.2012, 11:05

Hallo zusammen,

Micha67 hatte im August gepostet, dass Ende 2012 bzw. Anfang 2013 in Deutschland eine Studie mit Ibrutinib starten soll..

Grüße, Stintino

Thomas55
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Thomas55 » 11.10.2012, 10:42

mmartins hat geschrieben:Hallo Stintino

vielen Dank für diesen Bericht. Das hört sich ja wirklich sehr vielversprechend an. Hoffen wir mal, daß diese neuen Medikamente bald auch nach Europa kommen, falls das nicht sowieso schon der Fall ist.

Viele Grüße
Michael
Hallo Michael,

wenn ich richtig informiert bin, müsste in Deutschland bereits eine Studie eines Kinasehemmers in Kombination mit Rituximab randomisiert laufen - über die Wirkweise habe ich ja vor einiger Zeit hier einen englischen Artikel übersetzt und eingestellt, wir sind glücklicherweise in Europa beim Thema Leukämie nicht hinter den USA zurück...Ich habe auch den Eindruck dass nach Jahren relativen Stillstandes in der Cll-Therapie sich einiges tut.

Gruß
Thomas

mmartins
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Re: CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von mmartins » 11.10.2012, 10:30

Hallo Stintino

vielen Dank für diesen Bericht. Das hört sich ja wirklich sehr vielversprechend an. Hoffen wir mal, daß diese neuen Medikamente bald auch nach Europa kommen, falls das nicht sowieso schon der Fall ist.

Viele Grüße
Michael

Stintino
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CLL-Forschung + Ergebnisse mit Ibrutinib

Beitrag von Stintino » 11.10.2012, 08:35

Hier für alle CLL-interessierten Leser zwei englischsprachige Artikel: einmal ein Link zum Newsletter der Global CLL Reasearch Foundation, wo Prof. Keating sich zu kurz- und langfristigen Zielen der CLL Forschung äußert (Stichwort "Moon Shots" Program)
http://campaign.r20.constantcontact.com ... -E27RM8%3D
und einmal ein Beitrag zu Ergebnissen mit Ibrutinib, erschienen unter dem Titel "New Agents, Durable Responses in CLL" zitiert von Medscape Hematology-Oncology (Link kann ich leider nicht mailen, da eine Anmeldung zum Portal gefordert wird) Wenn jemand Verständnisprobleme hat, bitte mailen. Vielleicht kann ich helfen.

Grüße, Stintino

__________________________________________
Hello. I am John Gribben, Professor and Chair of Medical Oncology at Barts Cancer Institute, Barts and the London School of Medicine in London, United Kingdom. Welcome to this edition of Medscape Oncology Insights on chronic lymphocytic leukemia (CLL). Today I would like to discuss several of the important CLL studies that were presented at the 2012 annual congress of the European Hematology Association (EHA) here in Amsterdam.
Impressive Responses to Ibrutinib

The clinical session today was dominated by very exciting presentations of clinical studies using new classes of agents in CLL. Dr. Susan O'Brien[1] presented follow-up data on monotherapy with ibrutinib. This is a small molecule inhibitor of a protein called Bruton tyrosine kinase (BTK), which is involved in signaling through the B-cell receptor. This agent induces impressive responses, and the novel data presented today were that these responses appeared durable with only 1 patient progressing on therapy and all other patients continuing on therapy for more than 1 year and having continuing responses, including complete remissions.

All patients, including those with deletion 17p, who usually fail to respond well to chemotherapy, were able to remain on therapy without progression. A feature of this class of drug is that patients first experience a rise in white blood cell count as the cells leave the lymph nodes. As the lymph nodes shrink, the lymphocyte count goes up. When this was first seen with this class of drugs, people were concerned that this was representing progressive disease. We are now aware that as these cells leave the lymph nodes the cells die off within the circulation, and as the patients remain on these therapies over time the response rates continue to rise.

Dr. Jennifer Brown[2] presented data today that this agent can be combined with bendamustine or rituximab. This combination was associated with an increase in the response rate, and the use of these 2 agents blunted the rise in lymphocyte count, so that we could see these responses without that early rise in lymphocyte count in the blood that occurs with monotherapy with this agent.
Promising Data on Dinaciclib, Navitoclax

Another exciting new agent is dinaciclib, which is a cyclin-dependent kinase (CDK) inhibitor. The studies presented from Ohio State led by Dr. John Byrd[3] demonstrated that this drug is effective, and they have established the dose from phase 1 studies that are now going to enable this drug to move forward into definitive studies with this exciting class of agent. We have seen very impressive responses, including tumor lysis syndrome, with this class of agent suggesting that, in common with other CDK inhibitors, we have to consider the use of the agent very carefully in patients who have very high white counts or bulky lymphadenopathy.

The last class of drugs was described in 2 presentations on BCL2 inhibitors. BCL2 is the protein that keeps cells alive and is overexpressed in CLL and many other cancers. Navitoclax (ABT-263) could be combined safely with fludarabine/cyclophosphamide/rituximab or bendamustine and rituximab, and data were shown for that combination today.[4] However, Abbott's (Abbott Laboratories; Worcester, Massachusetts) new agent (ABT-199)[5] was shown to induce very impressive responses without inducing the low platelet count that had been a feature of ABT-263 treatment. This agent is now entering the next phase of clinical trial development in combination with anti-CD20 monoclonal antibodies.

The reason for the excitement in the field is that after years of using the same kind of agents we now have a large number of new agents that show great activity in CLL. The challenge that we as a community now face is how we are going to design and carry out the trials required to get these exciting agents available for our patients so that they are not only available within clinical trials but can really move the field forward. With that, I would like to thank you for joining me for this edition of Medscape Oncology Insights. This is John Gribben reporting from EHA 2012 in Amsterdam.

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