Dr. Christine Lovly at ALKtALK

Editor’s Note: A special thanks to Marc Rosenzweig for creating and scheduling the ALKtALK programs. Alice Chou graciously committed her time to transcribe thisALKtALK with Dr. Lovly so that it would be available here for other ALK patients. Thank you so much Alice Chou for your hard work and generosity!! . . and a big thank you to Dr. Lovly for spending her Sunday evening with our group answering these questions.

Dr. Christine M Lovly, MD, PhD at Vanderbilt-Ingram Cancer Center, Nashville, TN

Her studies concentrate on: Lung Cancer, EGFR, ALK, kinase fusions, acquired resistance, targeted therapies, tyrosine kinase inhibitors (TKIs), genomics, EGFR mutation, Small Cell Lung Cancer, Liquid Biopsies, Structural Biology, Precision Medicine

There was a survey for the audience.

About 26% of the attendees have had chemotherapy as part of their treatment.

Dr. Lovly took us on a virtual tour of her lab. Please watch: https://www.youtube.com/watch?v=kIORcslqaOE from about (6:45 to 23:30)

Experiments were performed in the lab to find commercially available drugs and test which medication can kill ALK+ cells. The team have found Aurora kinase inhibitors are good at killing ALK+ cells. Aurora kinase is a protein important in mitosis (where cells are duplicated) for normal growth.

The tests have also focused on figuring out the lowest level of medication that can be given to achieve the highest possible rates of killing cells.   

The technology used is called “RNA heat map” and is aimed at understanding what RNA is upregulated in an ALK cell line.  What is changed at the RNA level that can cause ALK resistance to a TKI? 

The team has found a protein called clusterin. Clusterin can protect cells from apoptosis. If clusterin is present, then the cells find it harder to die. The team has found that aberrant ALK is upregulating clusterin, so they have been trying a technique called “gene knockdown” to eliminate clusterin in a cell-line model.  It was observed that when clusterin was knocked down, the cells died. 

Dr. Lovly’s No.1 Doggie fan, Teagan (a cute dog), is also on a targeted medication because he has a mast cell tumor. This Dog Mom believes in TKIs so much that she is giving them to her dog!

Questions and Answers

General questions: 

Q: There are a lot of questions related to therapies not related to Western medicine such as massage, chiropractors, acupuncture, organic supplements, and yoga. What are your thoughts on this?

I cannot give you a good answer. There are no clinical trials that I can point to.  This is my own personal opinion. Why not? If massage makes you feel good; if acupuncture makes you feel better, then I do not see any harm in it.

If you are talking about chemicals or drugs that you are ingesting, that is a different scenario.  What I usually tell my patients is: if you are taking something over the counter, just let me know.  It is not judgmental.  I just want the medications and supplements to not interfere with each other.

I personally think massage, acupuncture and yoga really help with one’s mind and body.  So I do not see a downside to those things.  Anything in moderation is probably okay, but I really do not have a good data-based answer. 

Q: What about essential oils and diffusers? What are your thoughts? Are those okay for people to use?

I don’t have a great answer to this question. You will inhale vapors in the air. I know some essential oils may have some medical properties, but I do not know what those effects are. I really don’t know the effects such as how much and over how long. In moderation it is probably okay.

Q: What about the Covid vaccine as cancer patients? How can we get it faster?

I will answer that in two levels: what I see and what I know. I see huge variability. My patients are from different states. From every lung cancer organization that I belong to, foundations have been pushing agencies to prioritize lung cancer patients for the vaccine regardless of age because of the inherent risk of Covid and lung cancer. There will be a letter going out from across all lung cancer advocacy groups to tell agencies that put out policies about this opinion.  A common question that I get is: when to take it? While I am still on therapies? What if I’m having chemotherapy right now? Do I get the vaccine before or after treatment?  My answer and that of the large consortium of lung care doctors across the country is: Now.  If they offer it, take it. We don’t have any data on when is it better to get, is it before chemo? Or after chemo?  Right now, just get it.

Q: Is there potential for virtual clinical trials? What about the potential of telemedicine that we learned from Covid-19?

For sure, yes.  There are lessons to learn from the people who are doing telemedicine. There will be more virtual consenting, single-patient institutional review board (IRB). The IRB is a group of people that determines if a clinical trial is safe or not.  There’s a lot of paperwork that goes into making a clinical trial happen.  If an ALK patient is in Wyoming and cannot make it to a clinical trial site, then how can we get them on therapy? There is something called “single patient IRB” where you have approval to give someone experimental therapy. Secondly, you need to do some consenting.  Third is the delivery and oversight of the drugs.  There are companies being formed right now that will have nurses go out and administer therapy.  These same nurses can also monitor for toxicity and side effects and report back to the doctor. I am super excited to see this type of projects move forward. I am a big believer in “thinking outside the box.”  It is ridiculous to think someone has to pick up their lives and move across the country to get better cancer treatment.  It is not financially feasible, not obtainable, and not practical.  We can do better!  Medical care will shift after Covid. What will the timeframe be for that roll out? I am not sure.  Roche which makes Alectinib is running a trial. It is in conjunction with Foundation Medicine and Genentech, using Alectinib. Working with ALK+ patients (but not in the lung), can we give them ALK inhibitors (TKI) for various types of cancer? This trial will have remote consenting and nurses going out to visit patients.  Most of this trial will be in a virtual format.  This is a totally novel idea: bringing a drug to patients.  ALK+ medicine has just been opened to lymphoma patients. Why did it take so long? Because there was not enough patient data for lymphoma.  Right now at the clinic, if I see a patient who is ALK+ but has colon cancer, I cannot give them an ALK TKI because it is not FDA-approved.  

Combination questions

Q: Is there any preliminary data available that may predict which combination is more promising? Also, with combination clinical trials with various TKIs, which combination treatment is more promising? 

Combination trials tend to run slowly. First of all, every drug goes through phase 1. Every combination goes through a phase 1 trial.  You cannot just jump into the next step right away. You have to go back a few steps each time.  There are some other reasons for delays.  For example, there is some wait time for trials to start. Patients need to be screened and approved.  It is all about safety. When you have a combination of drugs, there will be more toxicity than one drug alone.  Currently, I am most excited about ALK &MEK inhibitor (Trametinib and Cobimetinib). I do not like Selumetinib because it tends to have more toxicity due to biochemical reasons. A lot of data is known about MEK inhibitors and the combination of MEK inhibitors in a melanoma setting is the standard of care.  We have a lot of data on how to deliver MEK inhibitors safely in combination. We have many preclinical data on ALK and MEK inhibitors in combination, they work better together.  Trials are underway.  We are investigating the combination in a 1st line setting where patients have not previously used a TKI, and using a combination when there is progression.  Hopefully, this combination will work in both settings and the toxicity is okay.  Another combination that I am excited about currently is the combination of an ALK inhibitor and a SHP2 inhibitor, made by Novartis.  This trial will probably go to Mass General in Boston. Just a little of my own comment: we need a unifying force across the US.  Having a clinical trial open in one location is great.  But to open up more trials across the US is even better.  This way we get more data faster and we can help patients better.  I would love to see more clinical trials to be more accessible to patients. 

Q: When will combination trials be open to all patients?  How can an oncologist facilitate patients to gain access to these combination trials? 

I cannot speak about combinations or any drug that is approved outside of the United States.  I am not familiar with EMA or the Japanese FDA. Every country will have a regulatory agency similar to USA’s FDA.  The biggest obstacle is to make the trials more available.  Not everyone can go to Boston, Tennessee, or California. 

Usually, if a single agency approves a drug or its combination, other regulatory agencies will quickly follow suit.  For example, if a drug is approved in the US based on US clinical trial data, then the data can also be evaluated in Europe, Japan, or China. It is dependent on different regulatory agencies.

Upcoming research: 

Q: What research for ALK are you excited to see coming up in the World Lung Conference? 

It is great to have good laboratory science, but you need to deliver it to the patients. Some studies in World Lung are centered on “real world data.”  Who is getting tested for ALK? How are they getting tested? We want to deliver effective therapy to everyone. If you are an oncologist, you ‘gotta’ find ALK. There are some places that still do not test for these mutations.

We want to be able to deliver what we have now to more patients. This will be the most impactful thing that will come out of World Lung.  

I expect to see lots of good science, lots of new combination studies, and lots of other great studies.  However, we need to deliver what we have right now before we can continue with what is coming down in the pipeline of research. I am a proponent for people to get the right testing done and for people to understand what they are being tested for.  

Q: It seems like biotech is accelerating research with CRISPR gene technology and NK (natural killer cells) cell therapy, but not much is heard from the academia side.  What about applying these technologies in the clinical setting? Can you explain some of these technologies?

CRISPR won the Nobel prize for 2020.  Very simply, CRISPR is to get rid of a gene and cut out a gene in a very strategic way.  CRISPR is the science to do that. This is something that viruses use that smart scientists figured out and utilize it for our purposes. We all use CRISPR as a part of our laboratory work.  However, for it to be delivered in the clinical setting is difficult. How do you get rid of a gene where you want to, but not in other area of the body? There are certain instances in rare diseases where this CRISPR technology has helped to resolve some of the problem.  This has not been done in any cancer yet, but we will get there.   

NK cells are another part of your immune system.  You’ve heard of B-cells which make antibodies and T-cells that fight an infection.  NK cells is another way that our immune system fights anything foreign such as bacteria, viruses, Covid, or your tumor.  NK cell technology is just adding another tool in our toolbox. Instead of thinking only about B-cells or T-cells, we can use NK cells as well.  There are some early trials using NK cells.  Most of these studies have been done in liquid tumors where cancer cells are floating in the blood. One of the main reasons is because it is easiest to deliver the treatment in the blood than to deliver it to a location such as in the lungs.  I do believe we will get there, but I am not an expert in NK cell technology.  I do not make NK cells in my lab, but in my lab there are people interested in this technology for small cell lung cancer.  It is very different from non-small cell lung cancer.   

I am also excited about a technology called BiTE therapy.  If you can imagine a way to make a T-cell that can link specifically to a tumor target. That is what BiTE therapy is trying to do.  These are also moving fast in the cancer world right now. 

Q: Do you feel federal funded research for lung cancer is fairly allocated? Should the pharmaceutical companies or academia be the leaders in this type of research?

We need the government because that is how our laboratories are run. We need big pharma because trials are mostly run by pharma due to the cost and infrastructure needed for a trial. I am biased but I don’t believe there’s enough funding.  You are talking about the number 1 cancer-related death in the US and worldwide. You cannot put enough smart minds and money to solve this problem. Right now, everything about cancer involves lung cancer: targeted therapy, immunotherapy, and early detection. 

I want to take a minute to talk about how the government funds the labs.  How long does it take for an NIH grant? If I write a grant today and submit it tomorrow, if the grant is funded at all, only about 8% (8/100) gets funded now. It takes at least one year before you see any money. That’s a long time in the research world. 

Q: A question about epigenetics. What is it? Does ALK have its own methylation/identification? Is it possible to find some early predictions by looking at the methylation of DNA in blood? And can alternative pathways be looked at in the blood?

Methylation is super cool. We talked about DNA to RNA to protein and there are many layers of regulation on all those processes. One way to regulate DNA is by methylation. It is like a tag on the DNA.  If you imagine DNA is a map, methylation is used to modify the map. For example, if you are going to the grocery store and your normal road is blocked, how do you get to the grocery store? There are many alternative routes to find a way around it. A lot of alternative routes cells gets to grow. One route is to change the location of a methyl group to change the look of DNA. This change can modify the whole cellular program. Not just one, but hundreds or thousands of them. You can detect this in your cancer DNA or you can detect it in the circulating tumor DNA.  I am really excited to use the methylation status in the blood to test for responsiveness of a treatment or resistance in treatment.  

I would really recommend looking at your scan the next time you are at your doctor’s office. Especially CT scans can be ambiguous.  Is it a tumor? A scar? A lymph node? Is it pneumonia? We need more regularity in the scans.  One way we can do better is to match the scan to changes in blood.  If the scan is ambiguous but you see changes in the blood, then that may make this situation more pressing. This may be confirmation that you are progressing.  I would like to see a complementary marker such as ctDNA with methylation status together with CT scans to help oncologists to detect better. ctDNA is just circulating DNA shed by the tumor cells in your blood. 

You can watch the entire video here: https://www.youtube.com/watch?v=kIORcslqaOE

The questions have been organized and are not in the same order as on the video.

Compiled and transcribed by: Alice Chou