About This ProjectCancer treatment is a challenging, complex and exhausting process for the patient, their family and medical team. Chemotherapy kills both cancer and normal cells, and may not prevent remaining cancer cells from spreading. Our research team believes that by turning up a gene HEXIM1, it has a way to stop most cancers from spreading. This could make cancer treatment more palatable and effective and ultimately make cancer a more survivable disease.
Ask the ScientistsJoin The Discussion
What is the context of this research?
- Malignant cancer is such a life threatening disease in part because the original tumor sheds cells which migrate to other tissues in the body, a process called metastasis. Thus cancer cells originating in the breast or prostate can spread to vital organs like the liver, brain or bone.
- Chemotherapy currently uses highly toxic chemicals to kill rapidly dividing cancer cells, but often it's a race against time to find a chemo drug to which the cancer isn't genetically resistant. Metastatic cells also generally resist other treatments like radiation.
- Modern cancer drugs are very sophisticated in being able to target a specific subtype of one variety of cancer. But this complexity makes cancer treatments expensive. Our drug could be used broadly as an initial frontline and cost-effective therapy.
What is the significance of this project?
Dr. Montano's lab studies a gene HEXIM1, which acts as a master control switch. Cells which have low levels of HEXIM1 divide rapidly, are likely to be cancerous and spread readily. Cells which are high in HEXIM1 are unable to divide or spread and are termed "differentiated". Typically differentiated cells form tissues and organs.
There are known chemicals called differentiating agents and some of these can increase the levels of HEXIM1 inside cells. One of these, HMBA, would be a useful chemotherapeutic drug, but has low potency and moderate toxicity. Dr. Montano and her collaborator Dr. Bin Su have made new HMBA-derived inducers of HEXIM1 with higher potency/lower toxicity for the treatment of multiple cancers including solid tumors such as those found in breast, prostate, lung etc.
What are the goals of the project?
Previously, we experimentally turned up (induced) HEXIM1 in mice either by genetic engineering or by administering the drug HMBA. We were able to inhibit the spread of breast cancer to the lungs in these mice, which are bred to have a highly aggressive form of breast cancer. Previous experiments with cultured breast cancer cells tell us which of the new HMBA derivatives induce HEXIM1 and are most likely to have high potency and low toxicity.
- Breed a new cohort of mice for the experiment so that we have meaningful numbers of test animals.
- Effective doses of the test drugs will be administered to the mice and the progress of disease followed under University approved ethical protocols.
- At the end of the study lungs will be examined for metastases and breast tumors for metastatic cells.
- The research team has designed new derivatives of HMBA which are promising new therapeutic drugs for cancer. Unlike drugs which kill cells, this class of cancer drug will turn up (induce) HEXIM1 protein in cancer cells that would normally spread (metastasize), instead causing them to differentiate and remain in their current tumor location where they are profoundly more treatable.
- The new derivatives have been synthesized and are able to induce HEXIM1 protein levels in cultured human breast cancer cells. But to apply for major grant funding for the drug development research, the effectiveness of the new derivatives needs to be shown in mice that are prone to breast cancer.
- The project's budget is now focused on amplifying the colony of cancer-prone mice and housing them while tumor growth is monitored after treatment
- Previous additional goals (tissue analysis etc) that we had budgeted are now being funded by Translational Research Funds from Case Western Reserve University! Thank you!
Meet the Team
Team BioDr. Monica Montano has been studying breast cancer for over 20 years. Since 1998 she has led her own lab as faculty at Case Western Reserve University in Cleveland, Ohio. Prior to this she completed a postdoctoral fellowship at the University of Illinois with Prof. Benita Katzenellenbogen (well known for studying hormones and cancer).
She earned her PhD in Reproductive Endocrinology from University of Missouri with Prof. Fred vom Saal (notable for his discovery of endocrine disrupting chemicals in plastics, like BPA). She still does benchwork daily, as well as guiding lab projects overall. Her lab is well trained in a wide variety of techniques and learns new ones as they 'follow the biology'.
The Montano lab was one of two groups to first identify HEXIM1, and the first to show HEXIM1's role in suppressing cancer, the main focus of this project.
Her 11 year old daughter is already interested in a STEM career and Monica promises to let her do her own Science Fair projects!
Press and Media
A university press release about our work on HEXIM1 was picked up by a national news agency because we showed that HEXIM1 not only prevents the spread of breast cancer but also results in a healthy heart. This means that while most cancer therapy drugs have very harmful effects on the heart, the drugs which we are developing to increase HEXIM1 levels should have beneficial effects on the heart.
These are sections of mouse lungs and the arrows show where cancer cells have spread from the breast of untreated "control" mice (top panels). However in mice either genetically engineered to express increased levels of HEXIM1 (bottom left panel) or treated with HMBA to induce HEXIM1 (bottom right panel), the lungs are relatively clear of tumor metastasis. More potent derivatives of HMBA should improve upon these results, as shown by the clear lungs of the genetically engineered mice (bottom left panel).
These images were adapted from a peer-reviewed publication by the Montano laboratory in the journal Oncogene, and which was published last year.
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