Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence
Abstract
:1. Introduction
2. The PI3K/Akt/mTOR Signaling Pathway
2.1. Regulation of the PI3K/Akt/mTOR Pathway in Normal Hematopoiesis
2.2. Constitutive PI3K/Akt/mTOR Activation in AML
2.3. Targeting the PI3K/Akt/mTOR Signaling Pathway in AML
3. Crosstalk of the PI3K/Akt/mTOR Signaling Pathway with Other Signaling Pathways in AML
4. Clinical Implications of PI3K/Akt/mTOR Inhibitors in AML
4.1. Buparlisib
4.2. Gedatolisib
4.3. Idelalisib
4.4. Dactolisib
4.5. MK-2206
4.6. Afuresertib
4.7. Uprosertib
4.8. Sirolimus
4.9. Everolimus
5. Clinical Strategies to Overcome Resistance to PI3K/Akt/mTOR Inhibitors in AML
5.1. PI3K/Akt/mTOR Inhibitors in Combination with Epigenetic Targeting
5.2. PI3K/Akt/mTOR Inhibitors in Combination with Bcl-2 Inhibitors
5.3. PI3K/Akt/mTOR Inhibitors in Combination with Kinase Inhibitors
5.4. PI3K/Akt/mTOR Inhibitors in Combination with DNA Repair Inhibitors
6. Conclusions and Future Directions
Author Contributions
Funding
Conflicts of Interest
References
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Compound | Manufacturer | Generic Name | Year | Target | Disease/Condition | Reference |
---|---|---|---|---|---|---|
Copiktra® | Verastem Oncology, Needham, MA, USA | duvelisib | 2018 | PI3K-δ PI3K-γ | Relapsed or refractory CLL, SLL, FL | [30] |
Aliqopa® | Bayer HealthCare Pharmaceuticals Inc., Whippany, NJ, USA | copanlisib | 2017 | PI3K-α PI3K-δ | Relapsed FL | [29] |
Zydelig® | Gilead Sciences, Foster City, CA, USA | idelalisib | 2014 | PI3K-δ | Relapsed CLL in combination with rituximab, relapsed FL and SLL | [31] |
Piqray® | Novartis, Basel, Switzerland | alpelisib | 2019 | PI3K-α | In combination with fulvestrant; hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer | [181] |
Afinitor® | Novartis, Basel, Switzerland | everolimus | 2009 | mTOR | Progressive, well-differentiated non-functional, NET of GI or lung origin with unresectable, locally advanced or metastatic disease | [182] |
Torisel® | Pfizer Inc., New York City, NY, USA | temsirolimus | 2007 | mTOR | Advanced renal cell carcinoma | [183] |
Rapamune® | Pfizer Inc., New York City, NY, USA | sirolimus | 1999 | mTOR | LAM, kidney transplant | [184] |
Investigational Agent | Condition | Phase | Status | Subjects | Study Period | Trial Number |
---|---|---|---|---|---|---|
gedatolisib | Therapy-related AML and MDS | 2 | Terminated | 10 | 2015–2018 | NCT02438761 |
buparlisib | Advanced Leukemias | 1 | Completed | 16 | 2012–2016 | NCT01396499 |
idelalisib | CLL, NHL, AML, MM | 1 | Completed | 192 | 2008–2012 | NCT00710528 |
Personalized kinase inhibitor therapy (dasatinib, idelalisib, ruxolitinib, ponatinib, sorafenib, sunitinib) + chemotherapy +/− monoclonal antibody treatment: (cyclophosphamide, cytarabine, doxorubicin, idarubicin, methotrexate, vincristine, rituximab) | ALL, AML | 1 | Recruiting | 24 | 2016–2019 | NCT02779283 |
dactolisib | ALL, AML, CLL with crisis of blast cells | 1 | Unknown | 23 | 2017–2017 | NCT01756118 |
MK-2206 | Relapsed or refractory AML | 2 | Completed | 19 | 2010–2018 | NCT01253447 |
afuresertib | Hematological malignancies | 1/2 | Completed | 73 | 2009–2012 | NCT00881946 |
uprosertib + trametinib | Recurrent or untreated adult AML | 2 | Terminated | 24 | 2013–2018 | NCT01907815 |
everolimus + midostaurin | AML, MDS | 1 | Active, not recruiting | 29 | 2009– | NCT00819546 |
everolimus + nilotinib | AML | 1/2 | Completed | 40 | 2008–2012 | NCT00762632 |
everolimus + cytarabine/daunorubicin | AML | 1 | Completed | 31 | 2010–2012 | NCT01074086 |
everolimus + cytarabine | AML | 1 | Unknown | 40 | 2008– | NCT00636922 |
everolimus + cytarabine/daunorubicin | Relapsed AML | 1 | Unknown | 21 | 2007– | NCT00544999 |
sirolimus + MEC | AML, myeloid leukemias, leukemia, CML | 1 | Completed | 16 | 2007–2010 | NCT00780104 |
sirolimus + MEC | AML | NA | Completed | 36 | 2010–2016 | NCT01184898 |
sirolimus + idaurubicin/cytarabine | AML, PEL | 1 | Completed | 55 | 2013–2019 | NCT01822015 |
sirolimus + azacitidine | (Recurrent) AML, de novo MDS, MDS with isolated del(5q) previously treated MDS | 2 | Active, not recruiting | 57 | 2013– | NCT01869114 |
sirolimus + decitabine | Relapsed or refractory AML | 1 | Completed | 13 | 2009–2012 | NCT00861874 |
Response | Criteria |
---|---|
Complete remission (CR) | Bone marrow blasts <5%; absence of circulating blasts and blasts with Auer rods; absence of extramedullary disease; ANC ≥1.0 × 109/L (1000/µL); platelet count ≥100 × 109/L (100.000/µL) |
CR with incomplete hematological recovery (CRi) | All CR criteria except for residual neutropenia (<1.0 × 109/L [1000/µL]) or thrombocytopenia (<100 × 109/L [100.000/µL]) |
Partial remission (PR) | All hematologic criteria of CR; decrease of bone marrow blast percentage to 5 to 25%; and decrease of pre-treatment bone marrow blast percentage by ≥50% |
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Darici, S.; Alkhaldi, H.; Horne, G.; Jørgensen, H.G.; Marmiroli, S.; Huang, X. Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence. J. Clin. Med. 2020, 9, 2934. https://doi.org/10.3390/jcm9092934
Darici S, Alkhaldi H, Horne G, Jørgensen HG, Marmiroli S, Huang X. Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence. Journal of Clinical Medicine. 2020; 9(9):2934. https://doi.org/10.3390/jcm9092934
Chicago/Turabian StyleDarici, Salihanur, Hazem Alkhaldi, Gillian Horne, Heather G. Jørgensen, Sandra Marmiroli, and Xu Huang. 2020. "Targeting PI3K/Akt/mTOR in AML: Rationale and Clinical Evidence" Journal of Clinical Medicine 9, no. 9: 2934. https://doi.org/10.3390/jcm9092934