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A PRECISION MEDICINE PLATFORM FOR ACUTE MYELOID LEUKEMIA TO HELP UNRAVELING THE MOLECULAR ADDICTIONS OF FLT3-ITD-DRIVEN AML
Author(s): ,
Pilar Ayuda-Durán
Affiliations:
Department of Molecular Cell biology - Institute for Cancer Research,Oslo University Hospital - Radiumhospitalet,Oslo,Norway
,
Beibei Zhang
Affiliations:
Department of Molecular Cell biology - Institute for Cancer Research,Oslo University Hospital - Radiumhospitalet,Oslo,Norway
,
Laure Piechaczyk
Affiliations:
Department of Molecular Cell biology - Institute for Cancer Research,Oslo University Hospital - Radiumhospitalet,Oslo,Norway
,
Mihaela Popa
Affiliations:
Department of Hematology,University of Bergen,Bergen,Norway
,
Dagim Tadele
Affiliations:
Department of Molecular Cell biology - Institute for Cancer Research,Oslo University Hospital - Radiumhospitalet,Oslo,Norway
,
Alexander Rowe
Affiliations:
Department of Microbiology,Oslo University Hospital - Rikshospitalet,Oslo,Norway
,
Joseph Robertson
Affiliations:
Department of Molecular Cell biology - Institute for Cancer Research,Oslo University Hospital - Radiumhospitalet,Oslo,Norway
,
Tobias Gedde-Dahl
Affiliations:
Department of Hematology,Oslo University Hospital - Rikshospitalet,Oslo,Norway
,
Emmet Mc Cormack
Affiliations:
Department of Hematology,University of Bergen,Bergen,Norway
,
Bjorn T Gjertsen
Affiliations:
Department of Hematology,University of Bergen,Bergen,Norway
,
Yngvar Fløisand
Affiliations:
Department of Hematology,Oslo University Hospital - Rikshospitalet,Oslo,Norway
Jorrit M Enserink
Affiliations:
Department of Molecular Cell biology - Institute for Cancer Research,Oslo University Hospital - Radiumhospitalet,Oslo,Norway
(Abstract release date: 05/18/17) EHA Library. Ayuda-Duran P. 05/18/17; 180642; E866
Dr. Pilar Ayuda-Duran
Dr. Pilar Ayuda-Duran
Contributions
Abstract

Abstract: E866

Type: Eposter Presentation

Background

Acute myeloid leukemia (AML) is an aggressive disease with poor prognosis (Tzelepis et al. 2016). No single driver mutation is present in all cases of AML, making its treatment a challenge (The Cancer Genome Atlas Research 2013). Current standard of care for AML is an aggressive cytostatics-based treatment that has remained unchanged for the past 30 years (Longo et al. 2015). Weak or elderly patients might not be eligible for intensive treatment, leading to poor survival rates. Many such patients are labeled as “untreatable”, although a portion of them could benefit from specific, individualized treatment. A precision medicine strategy can help to find the specific treatment for these ‘untreatable’ AML patients.

Aims
Drug-driven personalized medicine aims to directly test the sensitivity of primary cancer cells taken from individual AML patients to a selection of targeted cancer drugs, compare these results with drug sensitivities of healthy donor samples and select the most effective drug for each patient. This approach considers any combination of mutations or epigenetic changes that might not be found in the standard sequencing panels, an advantage when dealing with such a heterogeneous disease. Proof of principle of this strategy was recently demonstrated by FIMM (Helsinki, Finland) (Pemovska et al. 2013), not only providing immediate clinical benefit to leukemia patients, but also identifying drugs that can potentially be repurposed for future treatment of patients.

Methods

We have established a drug-driven personalized medicine platform for AML where we check the ex-vivo drug sensitivity and resistance of bone marrow primary cells to a panel of around 400 drugs and drug combinations covering the standard of care treatments, cancer chemotherapeutics as well as many clinically available and emerging molecularly targeted compounds. We calculate the IC50 values for all the drugs for each individual donor or patient, and then the differential drug sensitivity scores, selecting the drugs that affect preferentially the cancer cells when compared with healthy cells. To date we have successfully processed 6 healthy donors and 66 AML samples identifying subgroups of patients who respond with a similar dynamic to certain classes of drugs, as the subgroup of cells carrying internal tandem duplications in the receptor tyrosine kinase FLT3 (FLT3-ITD).

Results

FLT3 activating mutations, particularly FLT3-ITD, have been observed in approximately 30% of AMLs (The Cancer Genome Atlas Research 2013), and are associated with increased risk of relapse and poor clinical outcome (Abu-Duhier et al. 2008). The cellular pathways that support FLT3-ITD-driven cell proliferation and survival remain poorly understood. We discovered that FLT3-ITD-expressing AML blasts show an enhanced sensitivity to HSP90 inhibitors such as Ganetespib compared to healthy donors and any other subgroups of leukemia. In addition, HSP90 inhibitors specifically sensitize FLT3-ITD-expressing bone marrow-derived cells to TKIs, whereas cells derived from healthy donors are unaffected. HSP90 inhibitors also preferentially eradicate a population of patient-derived FLT3-ITD+ AML cells expressing leukemic stem cell markers.

Conclusion

In summary, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD-driven AML and provides a rationale for treatment of this form of AML with HSP90 inhibitors.

Session topic: 3. Acute myeloid leukemia - Biology

Keyword(s): Flt3-ITD, AML

Abstract: E866

Type: Eposter Presentation

Background

Acute myeloid leukemia (AML) is an aggressive disease with poor prognosis (Tzelepis et al. 2016). No single driver mutation is present in all cases of AML, making its treatment a challenge (The Cancer Genome Atlas Research 2013). Current standard of care for AML is an aggressive cytostatics-based treatment that has remained unchanged for the past 30 years (Longo et al. 2015). Weak or elderly patients might not be eligible for intensive treatment, leading to poor survival rates. Many such patients are labeled as “untreatable”, although a portion of them could benefit from specific, individualized treatment. A precision medicine strategy can help to find the specific treatment for these ‘untreatable’ AML patients.

Aims
Drug-driven personalized medicine aims to directly test the sensitivity of primary cancer cells taken from individual AML patients to a selection of targeted cancer drugs, compare these results with drug sensitivities of healthy donor samples and select the most effective drug for each patient. This approach considers any combination of mutations or epigenetic changes that might not be found in the standard sequencing panels, an advantage when dealing with such a heterogeneous disease. Proof of principle of this strategy was recently demonstrated by FIMM (Helsinki, Finland) (Pemovska et al. 2013), not only providing immediate clinical benefit to leukemia patients, but also identifying drugs that can potentially be repurposed for future treatment of patients.

Methods

We have established a drug-driven personalized medicine platform for AML where we check the ex-vivo drug sensitivity and resistance of bone marrow primary cells to a panel of around 400 drugs and drug combinations covering the standard of care treatments, cancer chemotherapeutics as well as many clinically available and emerging molecularly targeted compounds. We calculate the IC50 values for all the drugs for each individual donor or patient, and then the differential drug sensitivity scores, selecting the drugs that affect preferentially the cancer cells when compared with healthy cells. To date we have successfully processed 6 healthy donors and 66 AML samples identifying subgroups of patients who respond with a similar dynamic to certain classes of drugs, as the subgroup of cells carrying internal tandem duplications in the receptor tyrosine kinase FLT3 (FLT3-ITD).

Results

FLT3 activating mutations, particularly FLT3-ITD, have been observed in approximately 30% of AMLs (The Cancer Genome Atlas Research 2013), and are associated with increased risk of relapse and poor clinical outcome (Abu-Duhier et al. 2008). The cellular pathways that support FLT3-ITD-driven cell proliferation and survival remain poorly understood. We discovered that FLT3-ITD-expressing AML blasts show an enhanced sensitivity to HSP90 inhibitors such as Ganetespib compared to healthy donors and any other subgroups of leukemia. In addition, HSP90 inhibitors specifically sensitize FLT3-ITD-expressing bone marrow-derived cells to TKIs, whereas cells derived from healthy donors are unaffected. HSP90 inhibitors also preferentially eradicate a population of patient-derived FLT3-ITD+ AML cells expressing leukemic stem cell markers.

Conclusion

In summary, our study reveals a molecular basis for HSP90 addiction of FLT3-ITD-driven AML and provides a rationale for treatment of this form of AML with HSP90 inhibitors.

Session topic: 3. Acute myeloid leukemia - Biology

Keyword(s): Flt3-ITD, AML

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