• 2009-10 Student Proposals and Defenses
• Colloquium Series
• 2009 Research Showcase
• Faculty Spotlight
• PostDoc And Student Spotlight
  • Christina Kriegel
  • Thomas Koperniak
  • Lara Jabr-Milane
  • Christina Muratore

Lara Jabr-Milane

Lara Jabr-Milane wins the 2009 Boston Area International Society for Pharmaceutical Engineering (ISPE) Poster Competition

Lara Jabr-Milane is a PhD candidate working under the direction of Dr. Mansoor Amiji. While in Dr. Amiji’s laboratory Lara participated in the NCI/NSF funded pre-doctoral IGERT Nanomedicine fellowship program. Lara’s thesis project is titled. “Tumor Hypoxia, the Warburg Effect, and Multi-drug Resistance: Modulation of Hypoxia Induced Multi-drug Resistance Using EGFR Targeted Polymer Blend Nanocarriers for Combination Paclitaxel/Lonidamine Therapy”.

The clinical focus of Lara’s work is Multi-Drug Resistant (MDR) cancer. MDR cancer is most often implicated in cases of recurrent, non-responsive disease and is a significant obstacle in the treatment of cancer. Common treatment regimens accompanied by the non-specific character of traditional chemotherapeutics inadvertently foster the development of acquired MDR. As such, current treatment options do not adequately address the treatment of MDR cancer.

The biological focus of Lara’s work is to explore the relationship between the hypoxic microenvironment of a tumor, the development of MDR, and the energetic profile characteristic of the Warburg effect (aerobic glycolysis). As the vasculature of a tumor is highly irregular and ever-changing, regions of transient and chronic hypoxia are created within a solid tumor mass. These ephemeral states of low oxygen and nutrient deprivation are often accompanied by a change in the energetic profile of the cell. As described by Otto Warburg in the 1930’s, many cancer cells revert to high levels of aerobic glycolysis; this metabolic switch seems to confer many cellular benefits that aid in the survival and propagation of cancer cells. Lara has examined the cellular transformation and proteome changes that occur in response to hypoxia. She monitored the expression levels of hypoxia induced transcription factors (HIF-1α and HIF-2α) and targets of these transcription factors, including markers of MDR and glycolytic proteins (involved in the Warburg effect).

The therapeutic aim of Lara’s research is to develop an actively targeted nanocarrier system for combination(paclitaxel/lonidamine) therapy for the treatment of MDR cancer. EGFR was selected as the molecular target as this is overexpressed in many different types of aggressive cancer. Lonidamine was selected as it is a drug with treatment potential that failed clinical trials due to residual liver toxicity; this makes it an ideal candidate for nanocarrier delivery. Lonidamine is a hexokinase 2 inhibitor; hexokinase 2 catalyzes the first step of glycolysis and is associated with the mitochondrial outer membrane. Paclitaxel was selected to combine with lonidamine as it is a common chemotherapeutic agent with high residual toxicity; the therapeutic index of both agents could be improved through combined nanocarrier delivery. This drug delivery system actively targets a MDR cell by exploiting the expression of EGFR which is increased during MDR and is transcriptionally activated by hypoxia; this system treats MDR by inhibiting the Warburg effect and promoting mitochondrial binding of pro-apoptotic Bcl-2 proteins (lonidamine) while hyperstabilizing microtubules (paclitaxel). Lara is conducting a complete pre-clinical evaluation of this drug delivery system including in vivo studies evaluating the therapeutic efficacy, safety, biodistribution, and pharmacokinetic parameters in an orthotopic model of triple negative breast cancer.

In addition to her primary research, Lara is involved in many interdisciplinary collaborations. Lara is also an advocate for K-12 and community outreach; she developed the IGERT “Introduction to the Nanoworld” platform and is perpetually involved in the education of local youth.