Researcher - Dr. Laura Levy
Facility - Tulane University
Location - New Orleans, LA
Amount - 50,000
The Problem - The objective of our work supported by When Everyone Survives was to develop new therapies for leukemia and lymphoma, ideally using molecularly targeted approaches that kill malignant cells while sparing unaffected tissue. Specifically, our goal has been to expand the utility of a molecular target, protein kinase C beta (PKC), in the treatment of B-cell malignancy.
The Result - With the support of When Everyone Survives, we examined the effectiveness of inhibiting PKC in cells of two important B-cell cancers: Non-Hodgkin’s Lymphoma associated with AIDS (AIDS-NHL) and B-cell acute lymphoblastic leukemia (B-ALL) in adults.
What We Learned - Our findings are promising, and can be summarized as follows:
- Cells derived from AIDS-NHL and B-ALL express PKC in both major isoforms.
- Cell death results from treatment with inhibitor of PKC at concentrations that can be achieved in human serum.
- The molecular mechanisms by which PKC inhibition induces cell death were identified, and shown to be similar in both tumor types.
- The results indicate that PKC targeting should be considered as a potential therapeutic option in AIDS-NHL and adult B-ALL.
Our work led to two significant publications (N. Saba and L.S. Levy. 2011. Leukemia and Lymphoma 52:877-886; N. Saba and L.S. Levy. 2012. Journal of Investigative Medicine 60: 29-38, attached), in which the support of When Everyone Survives is gratefully acknowledged.
Where Do We Go From Here? - Our future plans will focus on B-ALL, where we believe that PKC inhibition will have the greatest impact. Precursor B-ALL is the most common leukemia in children and accounts for 20% of acute leukemia in adults. The intensive induction– consolidation–maintenance therapeutic regimens used currently have improved the 5-year disease free survival to around 80% in children and to 25%-40% in adults. The poorer response in adults is due to the inability to tolerate the intensive chemotherapy, and to the biology of adult disease, which is associated with poor-risk prognostic factors. Our initial work supported by When Everyone Survives indicated PKC targeting as a new and promising therapeutic approach. We have since shown that B-ALL cells representing the wide spectrum of the disease are sensitive to PKC inhibition at concentrations that can be reached in human serum. We are now dissecting the molecular pathways by which B-ALL cells are killed by the treatment so as to further refine the target. Our results have promise for the development of a novel therapeutic approach, much needed in B-ALL in adults.
Researcher - Dr. Eunice S. Wang
Facility - Roswell Park Cancer Institute
Location - Buffalo, NY
Amount - $50,000
The Problem - Acute myeloid leukemia (AML) is an aggressive leukemia affecting mostly older adults. Despite years of research, standard chemotherapy for AML results in overall survival rates of only 20-30%, highlighting the need for new therapies. AML cells primarily grow within the bone marrow. Recent data has demonstrated that the specific environment in which AML cells grow within the bone marrow is characterized by low oxygen levels (termed hypoxia). We propose that acute leukemia cells preferentially survive and grow under low oxygen conditions (hypoxia) by upregulating specific growth factors called hypoxia-inducible factors (HIF-1/2alpha). Our research will examine how these hypoxia growth factors contribute to acute myeloid leukemia growth.
The Result - Research conducted by Dr. Wang and funded by When Everyone Survives was presented at the American Society of Hematology annual meetings in 2008 and 2009 and published in the journal Leukemia Research in 2011. (Deeb G, Vaughan MM, McInnis I, Ford LA, Sait SN, Starostik P, Wetzler M, Mashtare T, Wang ES. Hypoxia-inducible factor-1alpha (HIF-1alpha) protein expression is associated with poor survival in normal karyotype adult acute myeloid leukemia patients. Leuk Res 35(5): 579-84, 2011).
What we learned - Our research taught us that overexpression of the hypoxia-inducible factor (HIF-1lalpha) was associated with poor outcome in half of AML patients and may play a role in the resistance of AML cells to standard chemotherapy drugs.
Where do we go from here? - Ongoing research in our laboratory is investigating whether drugs targeting HIF-1alpha and other factors promoting the survival of AML cells under low oxygen conditions can be effective in treating AML patients in the future.