Hassana Fathallah

Pharmacologic Induction of Fetal Hemoglobin Production

Reactivation of fetal hemoglobin (HbF) expression is an important therapeutic option in adult patients with hemoglobin disorders. The understanding of the developmental regulation of γ-globin gene expression was followed by the identification of a number of chemical compounds that can reactivate HbF synthesis in vitro and in vivo in patients with hemoglobin disorders. These HbF inducers can be grouped in several classes based on their mechanisms of action. This article focuses on pharmacologic agents that were tested in humans and discusses current knowledge about the mechanisms by which they induce HbF.

Pharmacological Induction of Fetal Hemoglobin: Why Haven't We Been More Successful in Thalassemia?

Abstract: The first studies of the pharmacological induction of fetal hemoglobin were conducted in patients with sickle cell disease and thalassemia. Although hydroxyurea was approved by the FDA for the treatment of sickle cell disease in 1996, no similar pharmacological agent(s) has been approved for the treatment of patients with thalassemic disorders. The small‐scale studies of the induction of fetal hemoglobin in thalassemia have been generally disappointing. The aim of this report is to provide a critical analysis of the factors that may be responsible for our failure to develop an effective fetal hemoglobin induction therapy for patients with thalassemia. We also describe several areas for future investigation that may be critically important for the development of an effective therapy for thalassemia.

Differences in Response to Fetal Hemoglobin Induction Therapy in β-Thalassemia and Sickle Cell Disease

Inducers of fetal hemoglobin (HbF) have shown considerable promise in the treatment of sickle cell disease (SCD). However, the same agents have shown less clinical activity in beta-thalassemia (beta-Thal). To understand the basis of these differences in clinical effectiveness, we compared the effects of butyrate and hemin on the expression of the different globin genes in progenitors-derived erythroid cells from patients with beta-Thal intermedia and SCD. Exposure to butyrate resulted in an augmentation of gamma-globin mRNA levels in both SCD and beta-Thal. Interestingly, butyrate exposure increased alpha-globin expression in beta-Thal, while alpha-globin mRNA levels decreased in SCD in response to butyrate. As a result, the favorable effects of the butyrate-induced increase in gamma-globin expression on alpha:beta-like globin mRNA imbalance in beta-Thal were reduced as a result of the associated increase in alpha-globin expression. Hemin had similar but less profound effects on all three globin genes in both categories of patients. Although the majority of patients with beta-Thal did not correct their globin imbalance in response to butyrate or hemin induction of HbF in a minority of patients resulted in marked reduction in globin imbalance. Thus, we believe that the poor clinical response in a majority of patients with beta-Thal to inducers of gamma-globin expression may be a reflection of unfavorable effects of these agents on the other globin genes.

Abstract A01: KRAS molecular profiling in non-squamous non-small cell lung cancer (NSCLC).

Recent studies suggest that patients with KRAS-mutant NSCLC fail to benefit from standard systemic therapies and do not respond to EGFR inhibitors. Therefore, there is a clear need for therapies specifically developed for these patients. Molecular profiling has the potential to identify potential targets that might provide a better treatment and novel targeted therapy for KRAS-mutated NSCLC. In this study, we purified RNA from archived tumor and normal lung tissue obtained from 20 patients with wild type (wt) and 17 patients with mutant (mt) KRAS tumors undergoing resection for stage I and stage II NSCLC, and assessed by reverse transcriptase-real time polymerase chain reaction (RT-PCR) the expression of four genes involved in DNA synthesis and repair including thymidylate synthase (TS), BRCA1, ECCR1 and RAP80, and the proto-oncogene SRC. Our results show that in mt KRAS tumors, the levels of expression of ERCC1, TS and SRC were significantly increased in comparison to paired-normal lung tissue (p ≤ 0.04). Expression of BRCA1 and RAP80 were similar in both mt KRAS tumors and paired-normal tissue. Furthermore, the expression of BRCA1, TS and SRC were significantly increased in wt KRAS tumors relative to their expression in normal lung (p ≤ 0.044). Expression of ERCC1 and RAP80 was similar in wt KRAS tumors and paired normal tissue. Interestingly, SRC expression in mt KRAS tumors was decreased in comparison to wt KRAS tumors. Our results suggest that greater ERCC1 expression in mt KRAS tumors might increase platinum resistance in this group of patients, whereas the greater expression of BRCA1 in wt KRAS tumors might be suggestive for the sensitivity to taxanes. Our data also suggests that the combination of a SRC inhibitor with a TS inhibitor such as pemetrexed might improve the outcome of patients with wt KRAS tumors. In conclusion, these results suggest that the most effective treatment strategy for KRAS-mutant NSCLC is combined targeting of oncogenic KRAS in addition to other therapeutic agents specific to the molecular profile of the tumor. Citation Format: Nagla Abdel Karim, Sandra Starnes, John Morris, Peter Pathrose, Ashley Perry, Hassana Fathallah. KRAS molecular profiling in non-squamous non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the AACR-IASLC Joint Conference on Molecular Origins of Lung Cancer; 2014 Jan 6-9; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2014;20(2Suppl):Abstract nr A01.