One of the central paradigms is that genes are located in isolated zones, minding their own business (making their own RNAs and proteins) and don’t usually cross talk with each other, except in pathological situations. For example, one of the hallmarks in cancer is DNA rearrangement, which results in the fusion of two separate genes. These gene fusion products often play critical roles in cancer development. Traditionally, they are thought to be the sole product of DNA rearrangement and therefore unique to cancer. This belief forms the basis for many cancer diagnostic and therapeutic approaches. Recently, we discovered two mechanisms that could generate fusion products without DNA rearrangement. One of the process is called “RNA trans-splicing”, whereby two separate RNAs can be spliced together and generate a fusion RNA, which then can be translated into a fusion protein. The other process involves two neighboring genes transcribing in the same direction, “cis-Splicing of Adjacent Genes (cis-SAGe). Our work on RNA trans-splicing and intergenic cis-splicing have posed a challenge to the traditional views and helped open a new paradigm for intergenic splicing processes that generate gene products in normal physiological conditions: even in the absence of physically “touching” each other, genes do send messages (messenger RNA) that can be mingled together.
Our long-term goals are to understand the scope of these phenomena, the physiological functions of these “intergenic splicing” process and their implications in both normal development and in cancer.
Other focuses of the lab are finding oncogene addiction events in glioblastoma (GBM), pediatric cancer, and breast cancer, developing novel drugs with minimal side effects. Recently, we have discovered a new cancer-driving gene, AVIL. AVIL gene is highly expressed in all the GBMs, but hardly detectable in non-cancer control cells and tissues. We have accumulated strong preliminary data supporting the premises that AVIL is an Achilles heel of GBMs, to which glioblastoma cells are addicted: AVIL is not only needed for GBM cells to survive and for tumor to develop in animal xenograft models, its expression is also correlated with patient survival. I Studies of the mechanism and its oncogenic effect will not only help us better understand the disease, but also lead to better treatment options.
The Li lab is supported by:
Dear Dr. Li: Forgive me if this is not the right way to contact you, but the UVA website doesn’t seem to give me a better alternative.
I am interested in the research, discussed in a press release today, showing genetic characteristics of glioblastoma. My father died of glioblastoma in 1989. My sister was diagnosed with glioblastoma in 2017, and an experimental treatment apparently knocked it out, so she is still here with negative MRI’s. But the fact that they both had a glioblastoma in essentially the same part of the brain has caused us to wonder about whether there is some genetic link at work, or whether it is simply unhappy coincidence. The popular accounts of your work with the AVIL gene shed no light for us. For obvious reasons, other family members very much want to know anything that can be known on this. Thank you in advance for any insights you can offer.
Hello Lloyd,
Thank you for reaching out to me. I am sorry about your family members’ illness. It is a devastating disease both to the patients and their close relatives.
I wonder if you have done whole genome sequencing to uncover potential mutations and structure variants. Genetic consular should provide you more information. I myself would want to know if your AVIL gene is intact. Since we just discovered the gene as a critical driver for GBM, there is not much known abut it. I am also not aware of any existing compounds targeting AVIL, or any clinical trials related to the gene. Sorry I can’t provide more insights.
Best,
Hi, we saw the article today about the work your lab is doing with glioblastomas. My mother had a glioblastoma removed a few weeks ago and we’re looking for clinical trials, are you running human trials or planning to start doing so soon?
Hello Katie,
Thank you for reaching out to me. I am sorry for your mom’s illness. It is a devastating disease for patients and their close relatives.
Since we just discovered the gene as a critical driver for GBM, there is not much known abut it. There is no current trials targeting AVIL, and I am also not aware of any existing compounds targeting AVIL. As a basic scientist, often times we have to wait for someone else to translate our discovery into clinical practice. However, this discovery prompted me to directly get involved in drug developing pipeline. As you may be aware, many oncogenes play key role in cancer, but not targetable. I am happy to report that AVIL is druggable, and we have a few lead compounds that showed promise. I do have to say that it is a long road ahead of us to get a final compound into clinical trial, which also requires a lot of resources. Please let her know that we are working hard on getting a treatment for her and other patients.
Best,
Hi Dr Li,
My husband was just diagnosed with a grade 4 glioblastoma. He is not able to have surgery as the tumor is too deep in his brain. I saw your article last week and of course this gave me hope. I know it’s new but I’m praying something happens to give him some hope to fight this. He starts radiation and chemo this week. Is there a way we can follow your findings and any updates?
Hi Hannah,
Sorry to hear about your husband’s illness. I wish we have had something for him already. Unfortunately, there is still a long way to go before our discovery can be translated into clinical practice. We will publish our results as we make more discoveries and progresses. We will try to update our website as frequent as we can. Thank you and hope your husband will do well in his treatment!
Dr. Li, many thanks to you and your lab for the magnificent discovery about the link between AVIL and GBM. Like Katie and Lloyd, I have a loved one impacted by GBM. My wife would be most interested in a Phase 1 trial regarding your research on AVIL.
Godspeed Dr. Li,
Chad
Hi Chad,
I am really sorry for your wife’s unfortunate encounter with GBM. At this moment, there is no clinical trial targeting AVIL. The lab people are all committed to work hard and speed up the research. We hope that someday soon our work can save lives in clinic.
Dr Li ,
I live in psl , FL where we are seeing high numbers of Glioblastoma. My husband passed this November at the age of 34. Around the same time 2 others were diagnosed All less than 45 & lived on the Same Street! 19 yrs ago Erin Brokavich was in our area for a pediatric brain cancer cluster . . With all ur Research is there any way you would have some insight OR since I have a handful of Glioblastoma Mostly Same zip code One of them being only 19… maybe some blood test to test all of the victims to see what exposures they have been exposed to? I really need some guidance.
Sincerely
Stephanie Ankiel (WiDow )
Dear Dr Li,
This is really great news. We have a lead cancer drug that is very effective on GBM. We are very close to starting a Phase1b/2 for pancreatic, GBM and brain mets. Kiyatec in Greenville, SC did some work for us and the compound did very well against 3 GBM pdx’s under their 3d ex vivo platform, even the one that was TMZ resistant. If you can contact me, we will provide our compound for your lab to see if our compound can hit the AVIL target, too If so, we are very far down the line and could help accelerate your research. Thank you and good luck!
Todd Robinson
trobinson@rokitpharma.com
Hi Todd,
Sure. We will be happy to test your compound. Thanks for reaching out to me. Please email me directly, hui.li@virginia.edu
Dr. Li,
My mother is days away from passing away from Glioblastoma Multiforme. Her wish was to be donated for medical advances. Can you direct me to the best place for brain donation? We live in Nashville Tn.
Thank you so much.
Lori
Dear Lori,
I am so sorry for your mother’s illness. I admire her courage and applaud her willingness to donate her brain to help research. Her legend will live on. Vanderbilt University should be a good choice.
Best,
Li lab
Dear Dr.Li
I found the news of your research project about glioblastomas, apparently, your research is located on the frontiers of the knowledge around the subject while there are lots of things yet need to be discovered.
You might be wondered to hear that I and my brother might be one of the rarest people whose parents both died because of glioblastomas, our mother, was diagnosed at the age of 34, passed surgery, and lived for about nine more years until the tumor recurred. and our father was diagnosed at the age of 61 with an aggressive form of brain stem glioblastoma and passed away after five months of hardship and struggle. they came from two different geographical and ethnic regions without no common ancestor, I don’t mean to be romantic and sentimentalized about this misfortune, but at least my decision about whether to drive my life toward having babies or not is really dependent on the scientific clear response to the very question: How prone we are to both inherit and transmit the disease to our children?
moreover, according to the genetic consular, genome sequencing showed no worrying point, but in my very personal belief, there has to be a more illuminating answer.
Best wishes.
Hi Dr Li,
Referring to GBM, are you familiar with the Tumour treating fields (TTF) approach? and its commercial application ( https://www.novocure.com ).
I know its a ‘ long shot’, but could the product(s) of the AVIL gene be somehow influenced by some kind of low power alternating electrical field?
Assuming proteins have charge ‘ topology’, could there be some kind of ‘selective targeting’ using an external force.
I don’t know or even begin to know how to know!
I would be very keen to learn your thoughts on TTF.
Many thanks for you time
Roger Moody.
Hello Dr. Li,
My husband is a patient at UVA with Dr. Schiff at the Cancer Center. Currently he is at 22 months from his resection of a pretty sizable GBM, grade IV, wild type tumor. He has just started regrowth in the top and bottom horn, not in the original site (which led to the brain stem). We had our surgery in St Louis, MI with Dr. Chicoine at Siteman Cancer Center on May 2, 2019, his feeling was that he was able to get a great deal of the tumor possibly up to 95% at that time. Physically my husband has been enjoying his life, he has had the loss of his memory, 80% eye sight right side and 20% left side. In telling you this I am wondering what was the treatment that prevailed while testing for an answer to the GMB question on the lab bodies, what is the process for the antidote, was surgery part of the procedure etc. I am sure that many of the people working towards making life possible and making it matter are wondering the same things, so aren’t you glad I asked? A lot of eyes are on you and your team right now. I can tell you that I have had multiple calls, texts, Inspire patients, nurses from all over the country are excited.
I would like to hear what your thoughts are for current trials reality (if at all). I appreciate your getting back to all of us. Hope is the most valuable words I can think of right now.
Sincerely, Cambridge Austin, wife of Brett A. Milton
Hello Cambridge,
Thank you for reaching out to us. Your husband is with good hands here (Dr. Schiff is one of the best). In terms of trials targeting the novel oncogene we discovered, there is none as of now. We are also not aware of any current drugs for this gene product. We are working on the drug developing part ourselves. We are glad and feel honored that our research can bring some hope to you and other families. Please know that you are not alone. There are many researchers like us are fighting this disease with you.
You are so kind, thank you for responding to us. I am (like many others) keeping a sharp eye out for all options. Sometimes it is someone like these family members who put the pieces together in their adventures of making the best of situation and finding a method that works best with their families goals in treatment. I hope that your work bears fruit, sooner than later for all those families living with GBM’s. Thank you, Cambridge Austin
Dear Dr.Li
You might be wondered to hear that I and my brother might be one of the rarest people whose parents both died because of glioblastomas, our mother, was diagnosed at the age of 34, passed surgery, and lived for about nine more years until the tumor recurred. And our father was diagnosed at the age of 61 with an aggressive form of brain stem glioblastoma and passed away after five months of hardship and struggle. Furthermore, they came from two different geographical and ethnic regions without any common ancestor.
I humbly want your professional advice about the subject how probable is it for my case to inherit the disease and more importantly to transmit it to the next generations through having biological children. Please answer these questions since morally it is significantly important for me to have a responsible decision.
Greatest regards and most sincere thanks.
Dear Javad,
I am sorry about your parents, and I totally understand the concern.I would exactly the same if I were you. Most of the GBMs are not inherited. That being said, I do recommend if you have concerns, talk to a genetic counselor. He or she will make suggestions on the relative risk, and recommend you to take whole exome or genome sequence. As our discovery is new, AVIL gene is not on the usual list of suspicion, but I am happy to look at the report once you have it.
Best regards,
Dear Dr Li,
I don’t know how to contact you besides leaving a comment, but I’m interested in becoming a member of this lab. I am currently a 2nd year student majoring Psychology. Women’s oncology has been an interesting area of topic to myself because of my family experiences that I would further like to learn about. If you could reach back out to me so that we can talk and discuss if this is a possibility, I’d greatly appreciate it. I look forward to hearing from you.
Alex Nguyen
ghh7cw@virginia.edu