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Uncovering Mechanisms Behind Tumor Suppression and Treatment Resistance

From left to right: Arifa Naya, GaoGuo, Yue Zhang, Amyn Habib, Xiaoyao Yang, Sansi Xing, Harshitha Balla

From left to right: Arifa Naya, Gao Guo, Yue Zhang, Amyn Habib, Xiaoyao Yang, Sansi Xing, Harshitha Balla

Glioblastomas (GBM) are the most common adult brain cancer with more than 300,000 cases diagnosed globally every year.  At UT Southwestern Medical Center, Amyn Habib, M.D., and his team within the Habib Lab are dedicated to uncovering the mechanisms behind therapeutic resistance and the invasiveness in GBMs. Dr. Habib, a Professor of Neurology at UT Southwestern and a Staff Physician at the VA North Texas Health Care System and Dallas VA Medical Center, has been leading this research since 2003. His robust team consists of an instructor, three postdoctoral researchers, a research assistant, and a UTSW medical student. Their innovative research and methodology have led to several peer-reviewed publications and 2 ongoing clinical trials.

Amplification of EGFR is a striking abnormality, as approximately half of GBM tumors exhibit these amplifications.” – Dr. Amyn Habib

The oncogene Epidermal Growth Factor Receptor (EGFR) is a primary focus at the Habib Lab. The amplification of the EGFR gene is a prominent genetic alteration. This abnormality is striking, as approximately half of GBM tumors exhibit these amplifications. These amplifications often result in further mutations that intensify the gene's activity. Researchers have sought to inhibit or block EGFR as a potential treatment strategy, but numerous clinical trials in this area have failed.

Why did they fail? Understanding treatment resistance was the key.

Blocking the EGF receptor triggers compensatory activation of alternative signaling pathways within the cancer cells, rendering the inhibition of EGFR ineffective. However, mouse models have shown that a combined inhibition of EGFR andthe Tumor Necrosis Factor (TNF) can overcome this treatment resistance.

Building upon this finding, an ongoing clinical trial is currently underway at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center to investigate this combined approach and is pending results.

Dr. Habib's research extends beyond GBMs, encompassing other cancers where EGFR plays a crucial role in treatment resistance. His lab has conducted extensive studies on lung cancer and other malignancies that exhibit similar EGFR abnormalities.

Another important question his lab addresses is the invasiveness of GBMs. While surgical resection is a common approach, it often fails to cure the tumor leading the team to explore the mechanisms underlying invasion and identifying strategies to suppress it.

In a surprising and exciting discovery, the EGFR was found to be tumor suppressive when activated by EGFR ligands with Tofacitinib demonstrating an ability to enhance tumor suppression (highlights from the publication below)

To further test this pathway, Dr. Habib’s team is currently collaborating with Dr. Michael Youssef from UT Southwestern's Neuro-oncology Department on a clinical trial. This ongoing research holds promise for developing novel treatment approaches for GBMs and potentially other cancers where EGFR is implicated in treatment resistance.

Dr. Habib and his team continue to delve into how these cancers develop and gain insights at the basic science level that will eventually help improve treatments and ultimately survival for those who are affected. Their ongoing efforts keep UT Southwestern at the forefront of pioneering research in this field, driving exciting advancements.

Highlighted Publication: EGFR ligand shifts the role of EGFR from oncogene to tumor suppressor in EGFR-amplified glioblastoma by suppressing invasion through BIN3 upregulation

  • Surprising finding: EGFR, normally considered a prime oncogene, is tumor suppressive.
  • Blocking EGFR can be detrimental; increased levels of receptor and ligands leads to increased activation which led to tumor suppression.
  • Overexpression of BIN3, a cytoskeletal protein that suppresses invasion, allows the tumor to remain compact and not metastasize.
  • Tofacitnib, a janus kinase pathway inhibitor, was found to strongly upregulate BIN3 in multiple GBM lines and inhibit invasiveness.
  • Other key considerations: the difficulty of quantifying the EGFR ligands expressed within GBM and the heterogeneity of the tumor.