if this holds for her2+ bc,humans,lapatinib,herceptin as well, would be breakthrough!

[Lani]

Chloroquin is a drug long approved and used against malaria

Leukemia

Blocking Cell Adaptation May Enhance Leukemia Therapy

By Charles Bankhead, Staff Writer, MedPage Today
Published: April 14, 2009
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine.
HOUSTON, April 14 -- The cell-killing potential of imatinib (Gleevec) increased by 50% to 75% when chloroquine was combined with the tyrosine kinase inhibitor, laboratory studies showed.
Chloroquine suppressed the adaptive mechanisms of autophagy that emerge in association with resistance to imatinib, Bruno Calabretta, M.D., Ph.D., of Thomas Jefferson University in Philadelphia, and colleagues reported online in the Journal of Clinical Investigation.

Similar results occurred when inhibitors of autophagy were combined with two other tyrosine kinase inhibitors, nilotinib (Tasigna) and dasatinib (Sprycel).

"The combination of a tyrosine kinase inhibitor . . . with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined chronic myelogenous leukemia stem cells," the authors concluded.

"Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of tyrosine kinase inhibitors in the treatment of CML."

Development of imatinib revolutionized the treatment of CML in chronic phase. However, clinical experience with the tyrosine kinase inhibitor revealed three limitations to imatinib-based therapy:

Limited response in CML-blast crisis or Philadelphia chromosome (Ph1) B-cell acute lymphoblastic leukemia (ALL) patients
Development of resistance, frequently caused by mutations in the BCR/ABL kinase domain
The relative insensitivity of Ph1 CML stem cells to imatinib
One strategy to overcome the limitations involves targeting autophagy.

"Autophagy is a process by which cells can adapt their metabolism to starvation caused by a decrease in metabolite concentrations or extracellular nutrients, a typical consequence of loss of growth factor signaling, allowing cells to evade programmed cell death," the authors noted.

Recent laboratory studies showed that treatment of experimental lymphomas with the autophagy inhibitor chloroquine led to reduced tumor growth in vivo, suggesting that induction of autophagy is a protective mechanism of tumor cells, they continued.

Moreover, autophagy inhibition has been shown to sensitize tumor cells to irradiation, aklylating agents, or arsenic trioxide, suggesting that autophagy is a self-defense mechanism in response to chemotherapy.

Studies of imatinib-treated cells have provided additional evidence that autophagy provides a survival mechanism.

Given the rationale for autophagy as a tumor survival mechanism, investigators studied imatinib-induced changes in CML cells.

First they demonstrated that treatment with imatinib induced autophagy in CML blast crisis cell lines, in CML primary cells, and in BCR/ABL-expressing myeloid precursors.

The studies also showed that imatinib-induced autophagy and imatinib-induced apoptosis do not have overlapping mechanisms.

To determine whether autophagy acts as a survival mechanism in their cell systems, the authors inhibited autophagy with chloroquine.

Treatment with chloroquine alone had no effect on cell death, but combining it with imatinib significantly increased the rate of cell death (P=0.024) compared with imatinib alone.

The authors examined the effects of autophagy and its inhibition in a mouse model of CML. Animals were treated with chloroquine, imatinib, or the combination two weeks after introduction of leukemic cells, when the bone marrow population had reached 30% to 40%.

Two days after completing treatment, the leukemic cell population had increased to 60% in untreated animals and to 50% in animals given chloroquine alone. Imatinib treatment reduced the population of leukemic cells to an average of 33%.

In animals that received chloroquine and imatinib, the proportion of leukemic cells in bone marrow had decreased to an average of 10.6%.

Investigators repeated studies using different autophagy inhibitors and different tyrosine kinase inhibitors. The results were similar to those obtained with chloroquine and imatinib.

The research was supported by the Medical Research Council of England, the Leukemia Research Fund in England, the National Cancer Institute, and the American-Italian Foundation for Cancer Research.
The authors reported no potential conflicts of interest.


Primary source: Journal of Clinical Investigation
Source reference:
Bellodi C, et al "Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells" J Clin Invest 2009; DOI: 10.1172/JCI35660.