Dr. Malkas: How a Bold Yes Became a Scientific Breakthrough | On the Edge of Breakthrough

[MUSIC PLAYING] Welcome to On the Edge of Breakthrough, where hope meets innovation in the fight against cancer.

[MUSIC PLAYING] Hi.

I'm Dr. Monty Pal.

I'm a medical oncologist at City of Hope.

And I'm really excited to bring to you On the Edge of Breakthrough-- Voices of Cancer Research.

We're going to be bringing some of our best researchers to the table to discuss exciting findings from their laboratories, from their research programs, and really get some great perspectives on what their plans are for the future.

Welcome everyone.

I am thrilled today to have the Dean of Translational Sciences here at City of Hope on the program.

Dr. Linda Malkas is a very accomplished scientist.

But we're actually going to start today, Linda, by talking about something a little bit different-- horses.

Oh.

What do you say?

Yeah.

Go ahead.

Go for it.

[LAUGHTER] Rumor has it that you're actually in charge of a total of 120 horses, have nine of your own.

Is that true?

180, and nine of my own.

Oh my gosh.

OK.

Now, tell me where this all began.

Well, I was never near a horse before I came to City of Hope.

And my husband tells the story better than anybody.

I always say, ask Bob how I got the horse.

And he'll say, well, only my wife can go to the hairdresser and come home with a horse.

And that's exactly what happened.

I was getting my hair done.

And the young lady who was doing my hair has her cell phone over my face.

And she goes, this is my mother's horse.

And I go, oh, nice.

And then she says, he's a dressage horse.

He's got all these ribbons and everything.

And I was like, oh, that's great.

He's beautiful.

And then she says, she can't keep them, but she loves him so much.

And I was like, yeah, I could see why.

And then she says, so I was telling her about all your dogs and cats.

And I thought, she's not going to ask me to take a horse.

And then she says, Mom wants to know if you want him.

And I don't know what it was.

I always say that it's a four-letter word that gets me in trouble all the time.

It's the word, "sure."

So I said, sure.

And so I'm driving home.

And I'm thinking, how am I going to tell Bob about this?

So I made him shrimp scampi that night.

OK.

[LAUGHS] And then, over dinner-- this is all I said to him.

I said, Bob, you know how I always loved horses?

And he went berserk.

It was the only big fight we had in 44 years of marriage.

But anyway, he's come a long way.

He's now turned into John Wayne and scientist at the same time.

Oh my gosh.

Well, I've got to get out there and visit.

Totally totally.

I'll take you riding.

You'll love it.

I do it all now.

Oh god.

It's so much fun.

And there's so many things I've learned about a horse.

They can tell your heartbeat from 4 feet away.

Hmm OK.

OK.

They're great discerners of people.

In about 30 seconds, they've totally sized you up.

It's been great in terms of even my research.

It's been great.

Wow.

Oh, that's phenomenal.

Yeah.

Well, so tell us about your origin story, then.

I assume maybe you grew up around horses.

Didn't realize this was so recent.

I saw that you've been on faculty at multiple institutions-- Indiana Maryland.

But where does the story begin?

How did you first get into science?

OK.

I'm a New Yorker.

It's in you.

They can't even extract it.

You hear it in my voice.

And when I get tired, or you get me really upset, it really comes out.

And so I grew up in Queens, New York.

I grew up in a two-room apartment.

And where we lived in Queens was actually, at that time, the cocaine capital.

And so my parents, who never went to college, but their whole thing-- they had two daughters.

And they stressed-- they said, education is the way out.

And they stressed that, stressed that, stressed that.

And they were right.

And my sister also has a-- she has a Doctor in Education.

So both their daughters grew up to take on STEM and education.

My father, who, though he never got to go to college, he loved space science.

And he used to take us to the Museum of Natural History in New York.

And the planetarium was there.

Many Sundays, we would go.

And you lean back in these chairs.

And at that time, they didn't have headrests.

So you were like cutting your head in there.

But we would look up, because in New York, there's so many city lights, you have five stars that you can see.

But with the planetarium, I could see the Milky Way.

And I was like, oh my gosh, I want to study that.

I want to go there.

So my first love was to become a space scientist.

So that's why I started in engineering school.

No kidding.

And then how did that ultimately lead to cancer biology?

You're going to love this.

I had to take a course in organic chem because-- and I'm one of those rare people that really loved organic chemistry.

Organic chem is the study of carbon.

And I think, at my heart, I'm always an engineer or an architect.

I'm like a builder.

And the beauty of the organic chem was, for the first time, I could see how chemistry was driving structure.

So you have the beautiful molecule of DNA.

And that is totally driven by positive-negative charges, hydrophobic-hydrophilic charges.

And it is totally chemistry driven.

I'm always amazed.

Sometimes you just stand back, and you look at the beauty of nature and the science.

And that's what's always driven me.

And the same thing for proteins, because proteins are-- they each have their own 3D structure, like a fingerprint.

Every protein has its own structure.

And that is all chemistry driven.

Well, I think we're going to get along really well, because my favorite class in college, I kid you not, was organic chemistry.

I had such a passion for it.

The thing I could never figure out is why inorganic chemistry didn't have the same appeal.

I don't know why that is, right?

Yeah it-- It's more mathematical, perhaps.

Maybe, or because, with organic chem, one chapter of the textbook kind of flowed into the other.

And you could see it building the big picture, whereas inorganic chem, it's like one chapter is so radically different from another.

So you don't get the big picture, but very important nonetheless.

It's so funny.

I was just thinking about sp orbitals, and enantiomers, and all this stuff that I learned back then that-- I'll tell you, the irony is it all has relevance today.

When I sit down and think about molecular pathways and so forth, it all comes back to organic chemistry, doesn't it?

It really does.

I switched majors, then, from engineering into chemistry, because I figured NASA would use chemists as well, right?

Sure, of course.

But I went on.

I really fell in love with this molecule of DNA.

And then the more I was learning about it, the more amazing it was.

So I always tell-- when I try to do my Miss Science thing for people, and I said, well, you know, just to get an idea of what an amazing creatures we are, if you take one human cell, and inside that cell is a nucleus-- I always say it that way.

I call it the house of DNA, right?

Yeah yeah.

And if you take all the nucleic acid, all the DNA, out of one nucleus of one cell, it stretches out to about 3 feet.

So if I took all of your cells, and I put all of Monty's DNA down here on the floor, Monty's DNA shoots out beyond the sun.

That's wild.

I'm experiencing the magic of DNA myself, because my daughter, who's 10, just did a big project on Rosalind Franklin, and the whole Watson Crick story, and what have you.

So it really brought me back to learning for the first time about DNA structure, function, et cetera, which is-- it's such, of course, a distant memory for me at this point, but still comes into play with everything that we're doing these days.

Even more so now, right?

Oh absolutely.

Absolutely.

Right.

Right.

So you started getting into DNA.

Was that in college, grad school?

When was that?

So I was in college.

Yeah, so I was in later-stage college.

And so my Bob-- remember, I'm a kid from Queens, right?

He was a graduate student.

Oh, no kidding.

And I signed up for undergraduate research.

And I was assigned to him as the graduate student.

And just for the audience, this is Bob Hickey, who's a tremendous scientist as well.

And Bob, who is a poor, suffering guy who's trying to get his PhD, and he's saddled with all these undergrads, and he's not a happy guy.

He would yell at us all the time.

Can you imagine?

Really?

OK.

Yeah.

I can't imagine that.

No, I know-- And he was always yelling, what are you doing?

Well, obviously, we were always attempting to blow up the lab, as far as he was concerned.

But I always say, the reason he married with me was because he could get reproducible data.

I swear to god.

OK.

OK.

Well, that's really important as a scientist.

Yeah.

Yeah, he got his PhD.

So I was working with him.

He was doing neuroscience at the time.

And we were doing these very complicated assays, radioactive assays.

And I was good at this.

And he says, Linda, you're pretty smart.

You should get a PhD.

And I was too embarrassed to tell him-- to say to him, I don't really know what that is.

And this tells you how true love works, right?

He went and got me the application to grad school.

And he goes, fill this out.

Oh wow.

And here I am.

Oh, that's awesome.

That's awesome.

And so tell me about grad school.

So what PhD program were you in?

What did you focus on there?

So I was in the City University of New York, their graduate program.

The program was biochemistry, molecular biology.

And I worked with Harvey Ozer, who was a wonderful virologist, actually.

So my area was cell biology and virology-- SV40, that was his virus-- because, you know, NASA could eventually use virologists.

So I was fascinated by that.

But the other thing that I got very interested in in graduate school was, again, back to this DNA, because everybody understands DNA replication, right?

Because you look in the textbook, and it's got like 10 proteins and stuff.

And everybody thinks it's all done, but not really, because here, you have 3 feet of DNA in a nucleus.

And every time a mother cell has to divide to two daughter cells, it's going to make a whole other 3 feet of DNA in a very crowded space.

And they do it inside of 8 hours.

And as an engineer, in my heart, I was like, how the heck do they do this?

So that led me-- so I got my PhD.

And I went up to New England to work with this fellow by the name of [INAUDIBLE], who wrote a paper where he proposed that DNA replication wasn't just carried out, Brownian motion or free random motion-- one protein comes in, does its thing, and leaves-- because we would never replicate our DNA in 8 hours.

Sure.

And so he proposed that there were multi-protein complexes that carried out DNA replication.

And I was like, I'm going to go look for that.

And long story, a lot of room-- now, I'm in Massachusetts, OK?

They have very cold winters.

And I spent four years in a cold room.

So literally, I was constantly in a winter coat.

I mean, in the summer, I was in-- Oh gosh.

Yeah.

But I did isolate from human cells a multi-protein form of what I called, at that time, a form of DNA polymerase that I could put into a test tube, offer it DNA, and it would make DNA in the test tube like it did in the cell.

Amazing.

And that launched my career.

And then I joined the University of Maryland School of Medicine.

And I could have been very happy studying replication forever.

But then I started reading about disease.

When you think about it, really-- you will agree on this-- all disease is a function of something wrong in DNA.

Sure.

Either it's mutation or damage.

No matter what disease it is, it arises from that.

I said, gee, I'm the mother of a replication complex.

I wonder if it's changed in cancer cells.

And long story short, the answer was yes.

We showed that this complex of proteins that I had looked at or had found was actually altered in breast cancer compared to non-malignant cells.

And that got a lot of hoopla.

And then we started ferreting our way through all the proteins in the complex to see who was different.

And in the meantime, I went up the food chain, as I call it, academic food chain, from assistant to full prof there.

The work that we were doing got noticed.

And one day, out of the blue, I get a call from someplace called Indiana University School of Medicine.

And they were very nice.

And they said, this company called Vera Bradley donated a bunch of money to create a new Chair of Molecular Oncology.

We would love for you to be the Vera Bradley Chair for Oncology.

OK, I'm a girl from Queens, all right?

I've lived in Massachusetts.

I've lived in Maryland.

They're both 3 hours apart from New York.

I'm OK, OK?

The Queens girl in my head, while they're on the phone, I'm going, Indiana.

Isn't that one of those rectangular states?

Right right.

It's a very California perspective on it, too.

These people were very smart, though.

They called me up a number of days later.

And they said, no pressure.

No pressure.

But we would love for you to come out to Indianapolis and just meet the people who donated this money, because we would like them to see the kind of person we're trying to bring here.

And I said, sure, because that's my four-letter word, right?

And so I fly out.

But they were very smart.

And what they had done was they had created this gorgeous gala, a beautiful gala.

It was like 900 to 1,000 people.

And they even had a bagpiper.

I mean, it was amazing.

Wow.

OK, this is a big deal.

It was a big deal.

A bagpiper.

And they go, but you can't leave until you meet everybody.

And I'm like, OK,.

So as I'm greeting everyone, I'm-- and this is how it went.

The entire evening was, hello, Dr. Malkas.

My wife died of breast cancer.

I have three daughters.

Dr. Malkas, my grandmother died of-- by the time the evening was over, I was like, where's the contract?

I'll sign it.

OK.

Oh wow.

Yeah.

Well, it's such a storied place for oncology.

I do GU cancers, kidney, bladder, testicular cancer.

And IU is where Larry Einhorn really made his name in testis cancer, and still a legend in the field.

Oh my gosh.

And I got to be in that department.

And it was wonderful.

I learned so much from them.

And so, while I was there, I worked with George Sledge, who was in breast cancer.

And together, we created the Breast Cancer Program for their Cancer Center.

And then I went on.

And I created a Signature Center that went across the whole IU-- so there's 13 units of IU.

And I was creating a translational program for breast cancer across all 13 units.

So you've built this really robust, impressive program at Indiana University.

And I guess the big question is, how did we manage to convince you to come over to City of Hope?

Tell me about that process.

It had to do with a photograph.

So you never know how life is going to-- you think you're on one path.

I know I'm going to sound very metaphysical here.

But it's been a very interesting path I'm on.

So I'm Miss Indiana.

And in fact, at the Indianapolis Airport, International Airport, I was the face.

So when you came in-- Oh, no kidding.

Oh OK.

--they had me with a bottle of dye.

This was the face.

I welcomed you to in science in Indiana.

I love it.

Good choice on their part.

Yeah.

And then Bob said it spooked him out because I was also over baggage carrier-- claim 5 and 9.

The newspaper there wanted to do a feature story on me.

And they were sending a photographer.

And we agreed on a date and time for the photographer to come take my picture.

And so the date and time comes.

And there's no photographer.

Half hour goes by.

An hour goes by.

No phone call.

I'm basically a New Yorker, right?

Two hours go by, and I'm like, OK.

OK.

And so I'm at my desk in my office.

I'm working on my big desktop computer.

And this man shows up in the doorway of my office.

And he's in his later 30s.

But he looks like a wreck.

And he's dropping his cameras.

And I'm so grateful I did not behave like a New Yorker.

And as opposed to yelling at him, I looked at him, and I said, are you OK?

And he was going to say yes.

But then he said no.

He said, my daughter, Ana, is across the street in the Reilly Children's Hospital.

She's 8 years old.

She has neuroblastoma.

She's had it since she was 3.

And we're running out of options.

Well, that took all the steam right out of me.

So we went and took a picture.

Anyway, he's wrapping up his cameras.

And he says, what do you do?

And I don't know what it was.

But I looked in this man's eyes.

And it really touched me that he was going to lose the love of his life, right?

And I also-- I had a flash that, what could I give him?

What is mine that I could give this man?

And I realized I could only give him one thing that is really mine.

And I go, come here.

Come here.

We go, and we sit down on my big desktop computer.

And I give him the only thing that is mine-- the work of these hands and maybe one or two bright ideas.

And I show him my data.

I show him tables of numbers, and graphs, and pictures of gels.

And I talk about the 3 feet of DNA, and how it's different in breast cancer versus normal cells, and all of this stuff.

Two hours go by.

And we get all done.

He goes, oh, I really wish you good luck, Dr. Malkas.

I said, oh, I wish you good luck.

His name is Steve.

I said, I really wish you good luck too.

And he left.

But I kept tabs on his little girl.

And she lost her life some months after that.

Eventually, I get a call out of the blue in my lab.

And he goes, hello, Dr. Malkus?

This is Steve Healey.

You probably don't remember me.

I said, oh, I remember you.

I'm so sorry.

And he says, you know, this is devastating, but can we come to your lab?

No kidding.

And I said, sure.

So I walk out to my lab.

And at that time, I had 19 people work for me.

And if you work for me, you're like-- I call you my kid, because I love you like you're my kid.

And I go, kids, these people have lost everything that means anything to them.

We're going to have a beautiful lunch.

We're going to have tablecloths and flowers.

And each of you are going to get up and talk 5, 10 minutes about what it is you do, because it's the only thing we can give these people who have lost everything.

So the day and time comes.

And I step out of my office, look down a long corridor, and I see Steve and a very pretty lady next to him.

I assume that's his wife.

And she takes one look at me.

And she starts to cry.

And I'm like, ay.

So anyway, we go.

And each of my young people get up.

And they talk.

And three hours go by.

And it's not that they're happy.

But she's not crying.

And we go to my lab.

And they're looking in the microscope.

And they're looking in my incubator.

And we're talking.

And then this changes the course of my life right here.

It's why I'm here, City of Hope.

He says, Dr. Malkas, thank you so much for having us here today.

And I said, thank you.

You're the reason we do what we do.

And he said, I know you do all this great work in breast cancer.

But if you could do something for neuroblastoma, it would mean the world to Barbara, his wife, and him, at which point he hands me a check for $25,000.

Oh.

Now, these are not rich people.

That's amazing.

Yeah.

Yeah.

He works as a photographer.

And she works for AT&T. And I'm looking at this piece of paper.

And I had grant money.

But this piece of paper, this was sacred money.

This was their heart.

And I wanted to do something bold in the name of that little girl.

So I work with Bob, my husband.

And I turn to Bob.

And I go, Bob-- and what I say to him is crazy.

It's crazy, because neither Bob or myself know how to do this.

Sure.

I go, Bob, you know how we've studied that this replication complex is different between normal and malignant cells?

And we've identified this funny protein called Proliferating Cell Nuclear Antigen, PCNA, which is different in cancer cells versus normal cells.

Bob, do you think we could make a drug against PCNA?

And then, if we make it to the form that's in the cancer cell and not in the normal cell, maybe it would only kill the cancer cells and leave normal cells alone.

And my beloved husband says, sure.

We don't have any clue.

Now, there's a very large pharmaceutical company.

So I thought, I'll call them up.

So I call up.

And I go, have I got a molecular target for you.

It's expressed in cancer cells, not in normal cells.

It'll be fantastic.

And they were very nice.

And they invite me over.

And it is a beautiful place.

I mean, it's all wood paneling.

And they were very nice.

They had assembled 30 people in this room.

And the head guy was there.

And they were very nice.

And I danced.

I showed them all my data.

I mean, I danced so hard to drive home how great a molecular target this was.

And I get through my whole talk.

And they said, Dr. Malkas, it's really elegant work you've done.

Very beautiful work.

But no one will ever make a drug against PCNA.

No one anywhere.

Why did they say that?

It's undruggable.

I never heard that word before.

Undruggable.

It has no enzymatic activity.

It's a protein that binds 200 other proteins inside the cell.

Now, I'm thinking, that's a great place.

That's like, if I shut down that activity in a cancer cell, I'm shutting down-- that's like a major hub.

But they're saying it has no enzymatic activity.

It's got a disordered region in it.

It's impossible.

OK.

I was so embarrassed.

I thought, oh my god, I have totally revealed, I don't know what I'm doing.

I slunk out.

But by the time I made the parking lot, I said, I don't know how I'm going to do this.

But I'm going to make a drug against that protein.

Awesome.

And then a miracle happens.

Someplace called City of Hope calls me up.

And they said, you know, we've been following your work in breast cancer.

It's really great.

And every year, we invite 15 people who are experts in their field to come and review all our research.

Would you be one of our external advisors?

And this is exactly what happened.

I had heard of City of Hope, but I didn't really know.

And I went, City of Hope, where are you?

OK.

Fair question.

And they went, Duarte.

And I went, what's Duarte?

That's literally what I said.

Right, where's Duarte?

What's a Duarte?

And they go, oh, Los Angeles.

I said, oh, I could do that.

So I flew out.

And in one morning, they totally blew me away, because, for the prior eight years, they had this crazy notion-- it might look crazy, but it was actually beautiful, because they assembled it.

And what they had been doing was hiring the talent and the skill sets, building infrastructure, creating shared resources, philanthropy, everything to help somebody who makes an observation on a lab bench to move it all the way to the clinic.

That is so true.

That is so true.

This is an evolution that I've seen during my time over here, where I think that perhaps the mold of City of Hope was very different when I started 20 years ago.

Within the past 10 years, it really is a place where you can do true bench-to-bedside research.

I was so floored.

I was like, oh my god, these are the people I need to work with.

And then, miracle of miracles.

That evening, they said, would you like to be our associate director for basic science here?

I didn't have to think twice.

So we came.

And I showed up.

I didn't tell City of Hope I had an undruggable target.

But I was coming here.

And I had to believe that everything they said they were was actually true.

Within three weeks, I was already working with Dave Horne, great medicinal chemist, and a lot of work.

I am so grateful.

When we got the first inkling of a would-be small molecule that targeted-- that I thought targeted my protein-- this is how unique City of Hope has.

It has its own internal regulatory system, a group.

Catherine Cortez and her team, as you know, handles 450 to 500 trials we do here at City of Hope.

So I go to her office.

And I'm like, I think I might have a small molecule.

And I would like to get it to trial.

And she goes, no problem.

She goes over to a filing cabinet.

And she pulls out a single piece of paper on it with all these lines.

She goes, do this.

And it was all the steps.

And it was like putting a recipe together.

Just my colleagues here, I am so grateful.

Everybody.

I would email-- talking to Tim Synold, Tim goes, well, Linda, you need to know how stable your molecule is.

He goes, well, it's great in your test tube.

He says, but once you put it into a person, the serum or the liver can just totally chew it up.

So-- I'm just going to briefly name some of these folks in the story so far.

So Dave Horne, Director of the Beckman Cancer Research Institute previously.

And he's, as you mentioned, a terrific structural chemist.

Tim Synold, wonderful pharmacologist who's been at City of Hope for three decades now.

Right.

Right?

And Catherine Cortez, really an important piece of this puzzle-- Absolutely.

--heads up our IND office for any investigational new drug coming through.

I wonder if you can give us the CliffsNotes version, because this is something I've always wondered about.

As a scientist, when you're taking a drug down that pathway, what are the steps?

You've developed this potential structure that might have some proprietary nature to it.

Walk us through what the next steps are.

You think you've created the small molecule.

You throw it on cancer cells versus normal cells.

Oh, it only killed the cancer cells on the lab bench.

And then it was like, I need to talk to some people who know how to do animal work.

And then-- and I have wonderful people.

The same people who came to my lab when I came here 13 years ago, they're still with me.

Oh, that's great.

I have the most wonderful team.

And [INAUDIBLE], who's in my lab, he had actually come from pharma.

So he was like, OK, I've got the animal thing.

And we piece it all together.

And another person that was very, very helpful was Dan Von Hoff.

I got to meet him.

And he says, you've shown that you can shrink some tumors in animals.

Now, what's the stability?

How long can it hold up in serum and in a liver?

Can you formulate-- formulation.

I'm dealing with a powder.

But it's got to be put into some kind of pill because it is an oral medication.

And then you work your way up to now, what do the FDA need to see in order to OK a trial?

They want to see the effects of your drug in different models.

So we send Catherine-- oh my gosh.

I think it was 1,500 pages, was the IND.

And she and her team-- Vincent Chung is leading that.

And I finally get the email from the FDA that we're OK to go forward with the phase I in solid tumors.

The very first people I sent that email to were the Healeys.

Oh, no kidding.

Aw, that's a great-- Now, the name of the drug-- --full circle.

--is AOH1996.

Remember, I said I wanted to do something bold in her name.

So it stands for Anna Olivia Healey.

Oh, no kidding.

And her birth year was 1996.

Oh gosh.

So as Steve answered me in that message, he says, now my daughter has a legacy.

So the second person I called was Dr. Von Hoff.

He goes, Linda, do you know what you did?

He goes, I'm going to send you something right now.

I want you to look at it.

So he sends me a file.

And it's a Gantt chart.

And Gantt chart is just steps.

It's like this big paper with all these lines.

And it was six pages long.

It was 350 steps.

He says, that is from when you named it all the way to the first patient.

He goes-- to the first patient.

He goes, you're on step 349.

OK.

And I was like, thank you, Dan, that you never sent me this before.

I don't think I would have ever gone forward with it.

But we went into clinical trial.

So the phase I is a dose escalation trial.

And you're looking for toxicity.

And we needed to reformulate for a while because it was getting to be too many pills that a patient was taking.

They take it twice a day.

So it's been quite an adventure.

And now, just been OKed for a brand new phase I trial now in AML.

It's going to be led by Amanda Blackmon.

Oh great.

Oh, I love Amanda.

She's terrific.

Oh absolutely.

One of the best hematologists, yeah.

And Guido Marcucci and Tran in his lab.

They work together.

And this is a whole new world I don't know from liquid cancers.

Their data is amazing.

The drug-- it's now out in the hands of people in Michigan, who are doing multiple myeloma, some studies in pancreatic cancer.

Kansas, they're looking in cervical cancer.

Wisconsin, there's people doing osteosarcoma.

The beautiful thing about having now stretched out all these other institutions is they're verifying everything that we had seen-- reproducibility.

Right.

Oh, I didn't realize that.

Oh, that's great.

And what can you share with us now?

I know it's early days for the trial.

But any preliminary results that are non-confidential that you can share with us?

Well yes.

What has come up that's been published is that AOH1996 works in combination with standard of care.

I'm seeing it in a whole bunch of different settings.

So in AML, the venetoclax standard of care-- you see boost in standard of care with AOH1996.

The groups out in Michigan-- they're at the Karmanos Cancer Center.

What they've been doing is, since AOH1996 is actually very benign to a patient, what they-- and because they see such a boost when in combination with standard of care-- and the people in Kansas as well-- what they've shown is they can-- and this is all, of course, in models, animal models.

Sure, of course.

But they can lower the dosage of standard of care in the presence of AOH1996 and still get a very effective killing of tumor.

Got it.

OK.

So AOH1996's home is going to be in augmenting standard of care, lowering the dosage of standard of care.

So in fact, standard of care becomes more benign for the patients.

The group in Kansas, with their cervical cancer data, are looking at a platinum compounds.

And Mustafa Raoof, he had a press release, some very lovely data out of-- this is the other thing about working here at City of Hope, is the joy of working so closely with the clinical side.

So Mustafa has done some very, very pretty work in pancreatic cancer.

We published this paper in Cell Chemical Biology to show that the mechanism of action of it was that it targets what they call transcription replication conflicts.

And it actually promotes additional TRCs in cancer cells.

And Mustafa just recently showed that in pancreatic cancer, this is an important mechanism for pancreatic cancer, as itself, as a disease state, and that our drug has an effect in there.

And he looked at some patients in our trial, our solid tumor trial.

And he saw some very nice results in there.

I don't want to steal any of his thunder.

No.

And I think I know the press release you're referring to.

He just had a nice paper out in Gastroenterology-- Right right right.

--which is terrific.

No, it really is such a great intersection of science and clinical work.

And getting somebody like Mustafa on board is just perfect, right?

Because he's got that expertise to harness the sample from the clinic, from the operating room, and then take that back to the lab and do something with it.

Absolutely.

It's like a brain multiplier here.

It really is.

When I was early on, trying to figure out-- because AOH1996, one of the things that the FDA wants to see is that, for sure, you are hitting your target.

And so Jeff Perry, he's a wonderful structural biologist.

And he took the molecule.

And he worked for two years.

And this was part of our application to the FDA.

He worked for two years, trying to see if our drug actually bound PCNA.

And it was very hard because-- and actually, nobody's ever done what he did before, because, remember, I told you that part of it-- it has this denatured part of the protein.

So it flops around.

So it's really hard to show that the drug binds there.

So he worked for two years.

10,000 crystals, he went through.

Oh, my gosh.

One night, like 3:00 AM in the morning, and he was up at Berkeley, up at their machine up there for all this stuff.

And he says, eureka.

I'll tell you in the morning.

And he beautifully showed that we went right into the pocket of PCNA with our molecule.

Very beautiful.

I mean, that was the clinchpins for how important-- really clinched the publication and for the FDA.

We really are binding our targets.

This is like that famous Rosalind Franklin photo, right?

Yeah totally.

To get back to the structure of DNA, right?

Oh, my gosh.

And it really does-- that huge X-ray crystallograph that really kind of made things click for Watson and Crick.

And he had a wonderful graduate student, Jennifer [INAUDIBLE], who now is still in his lab.

This story has just grown, because we've learned so much about that pocket.

It's the collaborations here.

Like, your brain gets bigger and bigger, just because you are in an environment where we talk very freely with each other.

You know what I say?

Literally-- remember, I wanted to be an astronaut, right?

I always say City of Hope is my NASA.

Oh, I love that.

That's great.

It truly is.

I mean, it launched-- I get to-- I'm also a big Star Trek fan.

I get to boldly go where no one's gone before here.

Oh, that's so terrific.

You mentioned Vincent Chung, who's now heading up a lot of our phase I efforts, terrific clinical pancreatic cancer researcher.

Absolutely.

Question I have for you is, now Vincent's got the drug.

It's in that phase I clinical trial.

What's next for your lab?

What are you focused on now?

Yeah.

So we have-- well, Bob Hickey, who's a wonderful chemist, he and [INAUDIBLE], fantastic medicinal chemists.

And they are just making analogs, making better AOHs, I would say-- a ton of them.

And so one thing is making the drug.

But you can also use these drugs as molecular tools for better understanding where it is binding, what is-- so one thing is about the small molecule binding in that pocket.

But also, what is happening in PCNA in terms of its conformation?

And since we found that AOH1996 is technically what they call a molecular glue, so these transcription replication conflicts-- it's great.

So you know you have active DNA replication complex making new DNA ch-ch-ch-ch-ch.

But at the same time, on the same DNA, you have active transcription complexes going along.

Eventually, these two big complexes hit each other.

Something we weren't planning on-- it wasn't-- because I came from this DNA replication, DNA repair background.

I said, OK, AOH1996 is that kind of inhibitor.

But in fact, something came out of it that we weren't anticipating.

So you have these two big complexes.

And people have studied how they resolve each other, get by each other to continue their jobs.

So it turns out that our molecule captured a moment.

So PCNA is part of this replication complex.

And you stick in the AOH1996 there.

And then that transcription complex comes along.

And what happens is, there's a moment when PCNA touches the small subunit of the transcription complex, RNA polymerase II.

And our drug makes it stick there.

Oh OK.

Interesting.

So a piece of the big transcription complex comes off, as well as the replication complex.

So you are now really mucking up a cancer cell.

It's very specific just to the cancer.

So we're really increasing damage inside.

And on top of it, because our drug also inhibits DNA repair, this damage can't get fixed in a cancer cell.

So the drug is actually like a-- I always think of Rocky-- a one-two punch, transcription replication complex, and I inhibit DNA repair.

So you make damage, and you keep it.

Awesome.

And I mean, that's so essential, to prevent mechanisms of resistance and-- So that's what we're studying.

And we're in collaboration with all these other labs that we're working with.

PCNA is-- there's only one gene for it in the entire human genome.

This region of the protein is actually conserved back to archetype bacteria.

It is critical, you know?

As I said, and it's also important for binding these 200 other binding partners.

So when our drug binds, what other pathways now are getting screwed up because PCNA is not functioning by binding into these other pathways?

When I came to City of Hope, it was about, can we make a molecule?

And then it was, can I get to clinical trial?

And I never thought beyond phase I.

It was like, if I can just get to trial.

But it's like, since we went to the clinical trial, it literally has blossomed to-- as my little nieces would say, into a gazillion other areas.

Very exciting for us.

That's great.

And it's a very logical progression, to go from AOH1996 to trying to find the 2.0 that interacts with other proteins and trying to optimize synergy.

I think it's a brilliant strategy.

Good approach.

One of the things that we're asking all of the guests that come through this program is that the title of our podcast is On the Edge of Breakthrough-- Voices of Cancer Research here at City of Hope.

What does On the Edge of Breakthrough mean to you, when you think about that title that we do in the podcast?

That is such a great title.

On the Edge of Breakthrough.

And then it plays into City of Hope as a larger institution, who we are.

And I've worked in many other fine institutions, very fine institutions.

The uniqueness of City of Hope, though, is-- and I mean this.

As a girl from Queens, I wouldn't say this if I didn't mean it.

We really do push the envelope here.

We really do.

I'm just one investigator here who's staying PCNA.

But we have so many other investigators who look at things just a little bit differently.

And the institution allows us to explore that.

But another very important arm of this is the philanthropy that is joined to City of Hope.

I have said to people, AOH1996 would never have been born if I didn't come here.

So I'm just one example of where we have literally-- just like Charles Yeager pushing the sound barrier-- we have so many investigators, you among them, who are literally pushing what we know currently for human benefit.

That is the breakthrough.

And sometimes it feels frustrating, like we're just taking baby steps.

But then you make this big jump, and another big jump.

I mean, I look at the people doing CAR T, and people doing viral oncolytics, and looking at different pathways and how they talk to each other.

So for myself, my breakthrough, what I think our contribution-- I just came up with this-- these combo standard of cares-- and I think AOH's home is going to be helping them to better, in a more kinder way.

So I say, we're going to be the olive in everyone's cocktail.

That's what I really think we're going to be.

Oh, that's a great way to put it.

I think that makes a lot of sense.

But if we didn't have City of Hope, this would never have occurred.

And I can look across the institution and say, how many-- the one thing about City of Hope, coming from New York-- and we have some very big-name cancer centers there.

And I thought, if those guys did some of the things at City of Hope does and never really talks about, they would have bronze statues in Central Park to them.

I swear to god.

But breakthroughs-- having all of these beautiful people and infrastructure, the capacity to make any kind of drug or therapeutic approach you could come up right here on campus, our internal regulatory pieces helping

assemble these trials, getting them to the FDA, all in one place-- I sometimes sit back, and I go, this is like the best kept secret.

It really is.

You're not the first person to say that on this program, actually.

We are a bit of a well-contained secret, previously, I would say now, with our national footprint.

Hopefully we're getting our name out there a bit more.

I'm very excited for the institution now, because it's-- we're pushing the barrier, the sound barrier here, for therapeutics, and personalized medicine, and all of these different things.

But now that City of Hope is actually moving across the nation and figuring out how to replicate our ability to deliver cutting-edge therapeutics here in Duarte, now across the nation, and making that-- this is like new templates people have to work out.

So it's a very exciting time, just not on the science or the clinical side, but on the bigger institutional picture as well.

Oh gosh.

This has just been phenomenal.

I can't wait to have you back to actually follow up and track the trajectory of AOH1996.

It is truly a beautiful story.

So thank you, Linda, for everything that you do.

And of course, thank you for joining us here today.

Well, thank you for this opportunity.

I really am-- I'm very honored to be here and to be part of this institution.

It's my NASA, you know?

I love that.

Thank you.

[MUSIC PLAYING] This podcast was produced in partnership with the Mays Media Labs.