Translational Cancer Research

Abde Abukhdeir, PhD - Breast cancers and ERBB2 protein

The research of Abde Abukhdeir, PhD, explores how early 25% of all breast cancers will express increased levels of the ERBB2 protein. These patients are candidates for trastuzumab therapy. Most women with elevated ERBB2 levels will respond to a combination of trastuzumab plus chemotherapy. Although most will eventually develop recurrent, metastatic breast cancer, there is a small subset of patients (~20%) who will respond to single-agent trastuzumab. Cancer is a genetic disease and the causes of drug resistance are likely also genetic in nature. My research is aimed at identifying the mechanism that sensitizes these patients single-agent trastuzumab, which would allow i) some patients to avoid unneeded chemotherapy and ii) the development of novel therapies to augment trastuzumab therapy.

Farrokh Asadi, PhD - Prostate cancer and androgen dependency

Research of Farrokh Asadi, PhD, examines how during early stages of prostate cancer, tumor cells are dependent on androgen as a growth factor and withdrawal of androgen results in apoptotic cell death and clinical remissions. However, tumor recurrences after therapeutic interventions are commonly associated with increasing androgen independence of the tumor cells and increasing resistance to pro-apoptotic and chemotherapeutic agents. Overexpression of interleukin-6 (IL-6) and parathyroid hormone-related peptide (PTHrP) have been implicated in prostate cancer progression and bone metastases. The interactions between prostate cancer cells and bone marrow derived mesenchymal stem cells (BM-MSCs) also appear to be critical in the development of androgen-independence and bone metastases. IL-6 induces the expression of PTHrP in human osteoblastic cells, a signature of androgen-independence and osteogenic differentiation of tumor cells. However, no studies have directly tested the IL-6 mediated PTHrP effects in prostate cancer progression. Previously, we have shown that the expression of PTHrP is enhanced in prostate cancer as compared with benign prostatic hyperplasia and is greater in poorly differentiated carcinoma as compared with the well-differentiated tumors. We have also reported that PTHrP is highly expressed in androgen-independent prostate cancer cell lines and the expression of PTHrP may contribute to the apoptosis-resistant phenotype in prostate cancer cells. Additionally, we demonstrated that the adenovirus E1A oncoprotein represses PTHrP promoter and mRNA expression in androgen-independent prostate cancer cell line. Furthermore, we have reported that E1A repression of PTHrP expression increases the caspase-3 activation and sensitivity of androgen-independent prostate cancer cell line to apoptosis triggered by tumor necrosis alpha. We hypothesize that: 1) IL-6 induction of PTHrP is crucial in tumor progression and androgen-independent growth of prostate cancer; 2) IL-6 inhibitors will repress PTHrP expression and provoke apoptosis in androgen-independent prostate cancer cells. Strategies to measure increased co-expression of IL-6 and PTHrP in prostate cancer patients may inform the development of clinical assays to reliably predict the prostate cancer recurrence.

Animesh Barua, PhD - Gynecological malignancy

Animesh Barua, PhD, does translational research on gynecological malignancy including ovarian, leiomyosarcoma (a form of uterine cancer) and cervical cancers.

Molecular markers for early detection of ovarian cancer, or OVCA

OVCA is a fatal malignancy of women. In most cases it is detected at late stages with <20% 5-year survival rates of patients. Survival rate increases remarkably (90%) when OVCA is detected at early stage. This project examines early changes in DNA damage repair mechanism associated with OVCA development to establish a non-invasive early detection test for OVCA.

Enhancement of resolution of ultrasound imaging for OVCA detection

Ultrasound imaging is the currently available non-invasive imaging method for the detection of ovarian abnormalities including OVCA. However, due to its limited resolution, ultrasound imaging cannot detect OVCA at early stage. In this project we are developing contrast agents for enhancing the resolution of ultrasound signals for early detection of OVCA.

Transition of Leiomyoma (fibroids) to Leiomyosarcoma

Uterine fibroids are common benign tumors of the uterus affecting around 70% of women of reproductive age. However, emerging information shows that a subset of fibroids transforms to malignant leiomyosarcoma. In this project we are examining factors associated with the transition of fibroids into leiomyosarcoma.

Jeffrey Borgia, PhD - High-throughput proteomic and genomic methodologies

Jeffrey Borgia, PhD, is focused on the use of high-throughput proteomic and genomic methodologies to better understand the biological mechanisms that underlie disease progression in patients with lung cancer. It is our ultimate goal to use these insights to develop improved diagnostic tools that aid physicians treating these people and promote improved quality of life and long-term survival. Working hand-in-hand with the physician groups at Rush, we use a range of technologies for these investigations that include Luminex-based immunoassays, novel immunoproteomic and quantitative proteomic methods for biomarker discovery driven by mass spectrometry, and expression proofing via RNA sequencing and/or microarray technology. Current research efforts focus on understanding the role of tumor metabolism in disease progression, discovery and characterization of surrogate biomarkers to better monitor aggressive tumor phenotypes, adoption of stem-cell like characteristics, and immune system monitoring. 

Vineet Gupta, PhD

Vineet Gupta, PhD, studies cell adhesion receptors, called integrins, and how they regulate a variety of biological processes.

Carl Maki, PhD

Carl Maki, PhD, focuses on how p53 is regulated normally and how this regulation is altered in cancer.

Deri Morgan, PhD - Proton channels (Hv1) as breast cancer treatment

Deri Morgan, PhD, looks at potential roles for proton channels (Hv1) as a treatment option in breast cancer:

Among women, breast cancer is the most frequently occurring cancer, accounting for 23% of diagnoses and causing 14% of cancer deaths.  More than 70% of cases currently involve surgical treatment, making it imperative that we explore potential new avenues that may yield less invasive means of attacking tumors. Late stage breast cancer, such as aggressive “triple negative” tumors currently have no treatment outside of chemotherapy and survival rates are poor. Triple negative breast cancers that do not express estrogen, progesterone or HER-2 receptors; these are the most common and effective targets for breast cancer treatment).  It is imperative that we discover less invasive and destructive methods to treat patients in late stages.

Recent studies have shown that highly metastatic breast cancer cells express the voltage gated proton channel (Hv1). This protein is NOT found in healthy breast tissue, it is something breast cancer cells are using to enhance their function.  Furthermore, greater Hv1 expression appears to correlate with larger tumor size, more advanced clinical stage, lower recurrence-free survival, and shorter overall survival.  Therefore, it is a promising target for intervention in advanced stage breast cancer such as triple negative tumors that have poor treatment options and prognosis.

The studies showed that inhibiting the expression of Hv1 suppresses proliferation of cancer cells, demonstrating its functional significance.  However, the mechanism by which Hv1 supports the survival of cancer cells remains unknown and therefore methods to exploit it in treatments are yet to be discovered.  Elucidating these mechanisms will lay the foundation for new targeted treatments. We hypothesize that Hv1 plays a role in regulation of intracellular acid production in advanced stage breast cancer. We postulate the expression of Hv1 in late stage tumors permits cancer cells to increase their metabolism, making them more aggressive and causing them to release more acid making their presence more hostile to healthy cells in the surrounding environment and makes the cell more likely to metastasize (spread to distant sites). We also postulate that the increase NADPH oxidase molecules in cancer cell together with the presence of Hv1 increases the oxidant production of the cancer cells that leads to biological toxicity making the cells more virulent.

Pratip Nag, MD - Transcriptional regulatory networks operative during cancer progression and metastasis

Pratip Nag, MD, focuses on understanding the transcriptional regulatory networks operative during cancer progression and metastasis. The active areas of research are:

  • Examining the regulatory role of Runx2 transcription factor in tumor growth and bone metastasis of breast cancer.
  • Understanding the relationship between deregulation of transcription factors and associated molecular and architectural abnormalities in early stages of breast cancer.
  • Investigating the silencing mechanisms of tumor suppressors by Runx2 in lung cancer progression.