Dasatinib prevents progression to lymphoid blast phase CML in mice, and may treat Ph+ ALL

[Guest guest]

The results of this study, done on mice, suggests that dasatinib (DS), due

to its ability to inhibit SRC family kinases in addition to bcr/abl, may

delay (though probably not prevent) progression of accelerated phase CML to

lymphoid blast crisis. It may also induce long term remission in patients

with BCR/ABL positive B cell ALL. We'll probably have to wait another year

to know whether this promise is fulfilled in actual humans. If so, it will

answer a question I posed the other day: whether SCR inhibition by DS has

clinical relevance.

More anon,

R

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[1990] Targeting BCR-ABL Kinase Activity-Independent Signaling Pathways and

Leukemia Stem Cells Is Essential for Curative Therapy of Philadelphia

Chromosome Positive (Ph+) Leukemia. Session Type: Poster Session 194-II

Shaoguang Li, Yiguo Hu, Swerdlow, Theodore M. Duffy, o Weinmann,

Francis Y. Lee . Research, The Laboratory, Bar Harbor, ME, USA;

Oncology, Bristol-Myers Squibb Company, Princeton, NJ, USA

Therapeutic efforts for Philadelphia chromosome positive (Ph+) leukemia have

focused on targeting mainly BCR-ABL kinase activity with kinase inhibitors,

since it has generally been believed that shutting down BCR-ABL kinase

activity will completely inhibit its functions, leading to inactivation of

downstream signaling pathways. Inhibition of BCR-ABL kinase activity by

imatinib mesylate (Gleevec) is highly effective in treating human Ph+

chronic myeloid leukemia (CML) in chronic phase, but not Ph+ B-cell acute

lymphoblastic leukemia (B-ALL) and CML blast crisis. The reasons for this

are not well understood, but the fact that imatinib is a strong inhibitor of

BCR-ABL kinase activity suggests that BCR-ABL kinase activity-independent

pathways also play a critical role in the development of both forms of Ph+

leukemia. We have previously shown that the SRC family kinases LYN, HCK, and

FGR are activated by BCR-ABL in pre-B leukemic cells and are required for

the development of B-ALL (Hu et al, Nat Genet 36:453, 2004). Others have

shown that cells from imatinib-resistant patients imatinib expressed an

activated form of LYN (Donato et al, Blood 101:690, 2003), and that a

BCR-ABL mutant with no kinase activity was still able to activate HCK

(Warmuth et al, J Biol Chem 272:33260, 1997). Based on these observations,

we hypothesized that inhibition of BCR-ABL kinase by imatinib might not

inactivate SRC kinases activated by BCR-ABL in pre-B leukemic cells, which

may explain the relatively poor activity of imatinib against Ph+ B-ALL and

lymphoid blast crisis CML. We find that SRC kinases activated by BCR-ABL

remain fully active in imatinib-treated mouse leukemic cells and this

BCR-ABL kinase activity-independent pathway is essential for leukemic cell

survival and proliferation. Blockade of this pathway also prevents CML

transition to lymphoid blast crisis. In mice with B-ALL, inhibition solely

of BCR-ABL kinase activity by imatinib is not curative, but inhibition of

both SRC and BCR-ABL kinase activities by the novel, oral, multi-targeted

kinase inhibitor dasatinib (BMS-354825), while not killing leukemic stem

cells, affords complete remission, maintained as long as treatment is

continued. In these mice, we identified the B-ALL leukemic stem cells as

B220+CD43+ pro-B cells. CML mice treated with dasatinib lived significantly

longer than those treated with imatinib, which correlated with significantly

lower numbers of BCR-ABL-expressing leukemic cells in bone marrow,

peripheral blood, and spleens of dasatinib-treated CML mice versus placebo-

or imatinib-treated mice. However, neither dasatinib nor imatinib were

curative in these mice, which was attributed to an inability of both drugs

to completely kill Lin-c-kit+CD34-Hoe- CML stem cells. Our studies indicate

that complete eradication of leukemic cells in B-ALL and CML mice requires

not only targeting BCR-ABL kinase activity-dependent and SRC-dependent

pathways, but also killing BCR-ABL-expressing stem cells insensitive to both

imatinib and dasatinib. However, the rapid and striking hematologic response

of B-ALL mice to dasatinib suggests that the pro-B progenitors with acquired

self-renewal capacity are the major source of highly proliferating

B-lymphoid leukemic cells in B-ALL mice, and that complete inhibition of

growth of this leukemic population with dasatinib could achieve long-term

survival in B-ALL.

Abstract #1990 appears in Blood, Volume 106, issue 11, November 16, 2005

Keywords: Chronic myeloid leukemia|Ph+ ALL|Leukemic stem cell

Date: Sunday, December 11, 2005

Session Info: Poster Session: Chronic Myelogenous Leukemia: Molecular and

Cellular Biology (9:15 AM-7:30 PM)

Presentation Time: 09:15 AM

Room: Hall B4

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