Integrative CML Therapies

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TR2-01789: Preclinical development of a pan Bcl2 inhibitor for cancer stem cell

directed therapy..............................................

" Cancer is the leading cause of death for individuals under 85. Relapse and

metastatic disease are the leading causes of cancer related mortality.

Anti-apoptotic BCL2 family member overexpression has been shown to promote

disease progression in both chronic myeloid leukemia (CML) and prostate cancer.

Andr., the emergence of cancer stem cells (CSC) promotes apoptosis resistance in

the bone marrow metastatic microenvironment. While targeted therapy with BCR-ABL

inhibitors has improved survival of patients with chronic phase CML, the

prevalence has doubled since 2001 with over 22,000 people living with CML in the

US in 2009. Unfortunately, a growing proportion of patients become intolerant or

simply cannot afford full dose BCR-ABL inhibitor therapy and thus, progress to

advanced phase disease with a 5 year survival rate of less than 30%. Although

prostate cancer prevalence was high at 2.26 million in 2007, distant disease was

relatively rare at 5%. However, like blast crisis CML, metastatic prostate

cancer survival was only 30% over 5 years. Overexpression of B-cell

lymphoma/leukemia-2 (BCL2) family genes has been observed in human blast crisis

CML and advanced prostate cancer and may fuel CSC survival. Recent RNA

sequencing data demonstrate that human CSC express a panoply of anti-apoptotic

Bcl-2 isoforms in response to extrinsic signals in vivo, indicating that a pan

BCL2 inhibitor will be required to abrogate CSC survival.

Notably, BI-97C1 potently inhibits growth of human prostate cancer in a

xenograft model as well as blast crisis CML CSC engrafted in RAG2-/- c-/- mice

while exerting minimal cytotoxicity toward bax-/-bak-/- cells. Because BI-97C1

inhibits all six anti-apoptotic Bcl-2 family members including Bcl-2, Mcl-1

(myeloid cell leukemia 1), Bcl-XL (BCL2L1), Bfl-1 (BCL-2A1), Bcl-W (BCL2L2) and

Bcl-B (BCL2L10) proteins, with improved chemical, plasma and microsomal

stability relative to apogossypol, we anticipate that it will have clinical

utility for targeting apoptosis resistant human CSC in two malignancies with

proven reliance on BCL2 signaling – blast crisis CML and advanced prostate

cancer.

Thus, anti-apoptotic BCL2 family member inhibition with BI-97C1 could represent

a vital component of a potentially curative strategy for advanced malignancies

that may obviate the need for costly continuous tyrosine kinase inhibitor

therapy by increasing sensitivity to therapy. Elimination of CSC contributing to

therapeutic resistance, the primary cause of cancer death, is of high clinical

importance and thus, development of a small molecule pan-BCL2 inhibitor would

fulfill a vital unmet medical need, fuel California biotechnology stem cell R & D

efforts and decrease health care costs for patients with cancer. "

" The reviewers agreed that, if successful, this proposal could have a

significant impact on the treatment of CML. Current therapies for CML are not

curative, presumably due to a reservoir of leukemic CSCs that can cause relapse.

Therefore, development of a drug that can kill dormant CSCs would have a great

impact on CML therapy. Reviewers did not find the scientific rationale for the

prostate cancer portion of the proposal to be particularly strong. They would

have appreciated more specific and compelling evidence for a role of BCL2 family

members in prostate CSC survival. Additionally there was doubt among some

reviewers that a role for CSCs in prostate cancer has been sufficiently

established. "

http://www.cirm.ca.gov/ReviewSummary_TR2-01789

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October 29, 2010 - NEW WEB PLATFORM ALERTS DOCS TO UPDATED GUIDELINES.........

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Purpose For New CML Trial - Ask your Doctor if you qualify...........

RATIONALE: " Dasatinib and vorinostat may stop the growth of cancer cells by

blocking some of the enzymes needed for cell growth. Giving dasatinib together

with vorinostat may kill more cancer cells.

PURPOSE: " This phase I trial is studying the side effects and best dose of

dasatinib when given together with vorinostat in treating patients with

accelerated phase or blastic phase chronic myelogenous leukemia or acute

lymphoblastic leukemia. "

http://www.searchmedica.com/resource.html?rurl=http%3A%2F%2Fwww.cancernetwork.co\

m%2Fchronic-myeloid-leukemia%2Fmashuptool%2FMashupTool_INSTANCE_a2X2%2F1390%2Fmu\

ltiPage%2F2 & q=CML+-+November+2010 & c=on & ss=cancerNetworkLink & p=Convera & fr=true & ds\

=0 & srid=1

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MORE AMERICANS ARE PAYING FOR HEALTH CARE WITH CREDIT CARDS....

http://health.msn.com/health-topics/articlepage.aspx?cp-documentid=100153442

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FROM THE LIBRARY OF MAYO CLINIC ON HOW TO LOWER YOUR HOSPITAL

BILLS............................

" Hospitals are notorious for making errors on bills, sometimes even charging for

surgeries that didn't take place, so of course you should review your bill

thoroughly. The problem: Hospital bills are so complex they seem to be written

in Greek. These folks can help decipher:

• The Patient Advocate Foundation offers free medical bill reviews.

• Gorillabill.com charges for medical bill reviews. It'll cost you at least

$200, and maybe more depending on how much money is recovered for you.

•Medical billing advocates also charge for their services. Here's a

state-by-state directory. Example: Medical billing advocate Jessie Maurer in

Des Moines, Iowa, found $3,000 in billing errors for the Trim family, whose son

was hit by a car and went to the emergency room.

" Whether your bill is big or small, it pays to negotiate, negotiate, negotiate

with doctors and hospitals. Click here for a free PDF version of the new book

" My Healthcare is Killing Me, " which offers tips on negotiating as well as other

hints on saving money on health expenses.

" Example: Hendrick, co-author of " My Healthcare is Killing Me " was left

with a $15,000 hospital bill after his wife gave birth prematurely to twin

daughters. Hendrick called the hospital, and his bill was immediately lowered to

$8,000. All it took was one phone call. "

http://www.cnn.com/2008/HEALTH/09/25/ep.cutting.health.costs/index.html

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