BACKGROUND:  Current approaches of targeted therapeutic intervention for a range of cancers and leukemias entail using small molecules and antibodies against a variety of molecule classes at the protein level. However, cancers that mutate into forms that confer resistance against such intervention remains an enduring challenge. Therapies directed against validated oncogenic genes at the transcript level may therefore represent a new strategy of cancer treatment that may be especially beneficial in cases of disease recurrence and resistance. Several strategic advances have been made regarding the efficient introduction and expression of different forms of RNAs such as short hairpin RNA (shRNA) and microRNA (miRNA) into mammalian cells and human patients. In particular, the use of lentiviral vectors has been demonstrated to be a robust method of directing specific knockdown of RNA transcripts of interest. Therefore, a potential therapeutic approach could consist of using a patient's own stem and progenitor cells to express miRNAs specific for an oncogene known to play a role in the manifestation of recurrent myeloproliferative or lymphoproliferative disease.

INNOVATION:  Researchers at UCLA have identified a method that allows for the robust expression of multiple miRNAs from a single lentiviral vector that targets a validated and clinically-relevant human oncogenic mRNA. In vitro assays used for the assessment of downstream signaling demonstrate that this strategy strongly disrupts the activity of the oncogenic target. In addition, strong apoptotic effects were observed in a cell line expressing both the oncogene and the selected miRNAs. Further results point to a mechanism that may consist of a reduction in the levels of target RNA and target protein levels through inhibition of translation. This strategy may therefore provide the basis for an autologous transplantation scheme using a patient's own stem and progenitor cells, thereby reducing the need for a matched donor allogenic transplant.

POTENTIAL APPLICATIONS 

• Treatment for various forms of myeloproliferative and lymphoproliferative disease in patients that display progression on currently available targeted therapies due to resistant mutations.
• Treatment for various forms of myeloproliferative and lymphoproliferative disease where no targeted chemotherapy is available but a clear target mRNA is known.

ADVANTAGES

• May represent a therapeutic strategy in patients where no HLA matched donor is available for allogenic transplantation.
• Few numbers of endogenous patient cells would be potentially required and a bank of patient cells could likely be used for later use for treatment of disease recurrence.
• Would offer an option to patients determined to be resistant to currently available targeted therapies.

DEVELOPMENT-TO-DATE:  Using an in vivo SCID mouse model, it has been confirmed that animals receiving cells containing both the target oncogene and the selected miRNAs survived normally without any leukomogenic presentation, while control animals succumbed soon after receiving cells expressing the target oncogene.

Related Papers (Selected)

• McLaughlin J, Cheng D, Singer O, Lukacs RU, Radu CG, Verma IM, Witte ON. Sustained suppression of Bcr-Abl-driven lymphoid leukemia by microRNA mimics. Proc Natl Acad Sci USA. 2007 December 18; 104(51): 20501-20506. [more]