Multiple myeloma is a plasma cell neoplasm that, despite recent advances, remains incurable and uniformly fatal. Recent advances in the understanding of the metabolism of malignant plasma cells have identified the autophagy pathway as an important mechanism of therapy resistance and therefore a potential therapeutic target. This proposarinvestigates the utility of adding autophagy inhibition to current effective therapies for myeloma. Proteasome inhibition using the novel agent bortezomib is now standard therapy for myeloma. The autophagy pathway is the major non-proteasomal mechanism for degradation of aggregated misfolded proteins and allows cells to escape the cytotoxic effects of proteasome inhibition, which makes combined inhibition an attractive strategy. Recent basic science laboratory work done by my collaborators has identified hydroxychloroquine as a potent inhibitor of autophagy in malignant cells. We have also shown that the addition of hydroxychloroquine to bortezomib results in synergistic killing of myeloma cells in vitro. These results justify investigation of the combination of hydroxychloroquine with bortezomib in patients with myeloma. Preclinical results have also identified the autophagy pathway as an important survival mechanism for malignant cells exposed to a wide variety of apoptotic stresses, including cytotoxic chemotherapy. The demonstration of increased autophagy in primary patient tumor cells after chemotherapy administration would justify a future trial of autophagy inhibition combined with cytotoxic chemotherapy. This research proposal therefore encompasses the following specific aims: (1) To determine, in a phase 1 clinical trial, the maximum tolerated dose of hydroxychloroquine when added to standard bortezomib therapy. (2) To determine, in a phase 2 trial, whether administration of hydroxychloroquine to patients with myeloma can inhibit autophagy in malignant cells and improve bortezomib efficacy. (3) To determine, in a prospective cohort study, whether administration of high-dose melphalan induces autophagy in malignant plasma cells purified from patient bone marrow samples. in addition, this Mentored Career Development Award is specifically intended to provide the Principal Investigator with comprehensive training in translational myeloma research to allow successful transition to an independent research career.

Public Health Relevance

. Multiple myeloma remains a deadly cancer that cannot be cured. This research seeks to improve two of the current most effective treatments for myeloma: autologous stem cell transplants and a newer medicine called bortezomib. The results will directly benefit patients with myeloma through a better understanding of how to increase the efficacy of current effective but insufficient treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23CA130074-04
Application #
8320298
Study Section
Subcommittee G - Education (NCI)
Program Officer
Lim, Susan E
Project Start
2009-09-22
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$172,368
Indirect Cost
$12,768
Name
University of Pennsylvania
Department
Biostatistics & Other Math Sci
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Vogl, Dan T; Stadtmauer, Edward A; Tan, Kay-See et al. (2014) Combined autophagy and proteasome inhibition: a phase 1 trial of hydroxychloroquine and bortezomib in patients with relapsed/refractory myeloma. Autophagy 10:1380-90
Garfall, A L; Dougherty, A L; Vogl, D T et al. (2014) Association between mobilization regimen and PFS after auto-SCT for multiple myeloma. Bone Marrow Transplant 49:1439-41