Marileila Varella Garcia, PhD: What Is an ALK Gene and What Does It Mean For Lung Cancer Patients?

Marileila Varella Garcia, PhD gives an overview of the ALK gene — what it is and what it means for the future of lung cancer treatment.

The Group Room at the 14th Annual World Conference on Lung Cancer (WCLC) was made possible, in part, by:

 

VIDEO TRANSCRIPT

Selma R. Schimmel, Founder & CEO, Vital Options International:

This is Selma Schimmel at the 14th World Conference on Lung Cancer, WCLC, which is organized by the International Association of the Study of Lung Cancer, the IASLC, in Amsterdam, the Netherlands.  Our discussion begins with Doctor Marileila Varella Garcia.  Welcome.  Doctor Garcia is Professor of Medical Oncology in the Department of Medicine at the University of Colorado, Anschutz Medical Campus in Aurora, Colorado.  Hello, Dr. Garcia.

Marileila Varella Garcia, PhD, Assoc. Dir. for Education, University of Colorado Cancer Center:

Nice to be here.

Selma R. Schimmel:

I’m happy to talk to you because you’re a research scientist and so much of what is happening in the area of lung cancer involves the identification of new pathways and these molecular components and genotyping of tumors… all of these areas that are influencing the treatment choices and the development of new targeted therapies for lung cancer.  These are very complex principles and what I’m hoping we can do with you is, in particular, talk about the ALK pathway but in a language that our audience can understand, and I think that you’re able to do this for us.

Marileila Varella Garcia:

My pleasure.  So we’ll try.  It has been very exciting to be a researcher at this time because a decade ago we thought we knew maybe almost all and we were about to cure diseases that are very severe.  And I think that now we are much more realistic because the big change that happened in this decade is that we all understood how little information we had, how few data we had to support our conclusions.  And we are understanding much better what happened inside of the cell that makes a cell being a tumor moving to a cancerous stage.  So it has been very exciting and I’m very pleased to be involved in this process.

Selma R. Schimmel:

You know, in the past the way we treated cancer, we bombarded the whole body.  You would take systemic therapy and fast dividing cells, whatever is in that path, they got zapped but today we’re really narrowing in on these targets and the unique biologic and molecular components of a given tumor and a given cancer.

Marileila Varella Garcia:

Exactly.  And we learned that some types of tumors are driven by specific molecules and the ALK, like you said, the ALK is a short name – ALK – is the short name for one gene; the long name is anaplastic kinase lymphoma.  So this gene that we use… for every gene we have a short name.  All the genes – we have about 30,000 genes – all the genes have long names and then we create a short name so we can kind of communicate easier with this name.  So ALK is the short name.

Selma R. Schimmel:

But you said lymphoma, so a listener might say, ‘lymphoma, well what does that got to do with lung cancer?’

Marileila Varella Garcia:

Exactly.  This gene was identified as abnormal.  In lymphoma, in 1994, in several types of lymphoma, not a single type, it was only identified, associated with a solid tumor, more specifically in lung cancer in 2007.  So a long period happened up to the first discovery with lung cancer showing that the particular set of lung cancer had derived from abnormalities in the ALK gene.  So, the ALK is a normal gene, everybody should have an ALK gene; as well as all the other genes that we have.  What happened is that every gene is not supposed to work every time, so the genes are timed during our life.  Some of them are better at doing their job during development.  Some of them are better when we are adults.  Some of them work everywhere.  Some of them only work in our eyes, or in our skin, or in our lungs.  So the ALK gene is a normal gene that is supposed to work during embryonic development, only when we are in formation, during our formation and they should be silent from that point on.

Selma R. Schimmel:

But then a gene has the ability to mutate.

Marileila Varella Garcia:

Yes, there is a specific mutation that makes the gene active again.  And how does it happen?  So, I used to tell my students that every gene has different components, and then I think I compared the components like body parts.  So the gene has a tail, has a central body part, it has a head.  So, why do we think that this part of the gene is called the head?  Because it’s the part that regulates the action of the gene.  The really parts that work is the body and the tail of the gene that really make the activities, whatever activity the gene is supposed to be doing.  But nothing happens if the head of the gene doesn’t say, ‘yes, you are allowed to work.’  So it’s the head of the gene that determines if the gene is going to be active or silent.  Right?  So, in a normal ALK the head tells, during development, that the body should work.  Then we have in the body of the gene, a domain, a specific domain that’s called kinase domain- and kinase is a very active reaction, triggers very active reactions.  So when the head says ‘work’, this kinase domain is activated and the protein is getting produced normally; produced, produced, produced.  When the head says, ‘shut up’, this stops; then protein is not produced.  Then, that’s the normal situation in an adult.

What happens in the lung cancer is that there is a break, a physical break, between the head of the gene and the body of the gene.  And there is a movement and another piece of DNA comes, infuses with this body of ALK, but this new head has a no-stopping message.  So this new head tells now the body, because now we have a mix, I have a new head for this body and this new head is telling you, ‘you should work, you should work, you should work’, so the protein gets produced again.  And if this mutation happens in an adult stage and happens in the lungs, that lung cell first, probably is confused and says, ‘are you sure?’  But that’s the message, so it starts producing protein and that protein allows the cells to grow without control and that’s the first marker for cancer.

Selma R. Schimmel:

So, once this confused process begins it doesn’t stop itself, it reaches the point of no return and that mechanism just keeps going?

Marileila Varella Garcia:

Exactly.  And it tells that the function, the active part of the gene it is under the control of a new head now and cannot get rid of that signal, so the signal keeps coming that they should be dividing.  And in the ALK specifically that it is a very interesting story because the most common head that comes to attach it to the body of ALK comes from one gene whose nickname is EML4- and EML4 is a gene that, in a normal cell, controls the development of microtubules.  So, what is a microtubule?  We have trillions of cells and our cells, most of the time, are dividing in a normal rate.  Some cells, blood cells divide faster than skin cells, some cells do not divide when we are adults.  But when the cells divide, to separate the 2 daughters… we have a cell that divides in 2. The 2 daughters are separated by microtubules.  So microtubules are critical molecules in the normal stages every time in our life.  So we always need microtubules everywhere.  So, when the microtubule gene is programmed to work ever, always.  So when the head of the microtubule gene is connected to the tail of the ALK gene that is supposed to be silent is when the problem starts, because this head gives the message that it knows what to do and that is to work.

Selma R. Schimmel:

Thank you, Doctor Marileila Varella Garcia.

Marileila Varella Garcia:

Thank you.

Selma R. Schimmel:

Professor of Medical Oncology in the Department of Medicine at the University of Colorado, Anschutz Medical Campus, Aurora, Colorado.

Marileila Varella Garcia:

Thank you.

Selma R. Schimmel:

You’re welcome.

END OF VIDEO

 

 

Comments