KRAS

I'm like, I'm putting an accent on it, but, um, he, uh, so I had heard it was like, he was very much like a celebrity to me.

He, he made KRAS druggable.

He broke through the, he made the undruggable druggable.

So it was this like this big, you know, exciting thing.

So I'll dive into more details about that.

But he won the prize.

And so that basically gave me an excuse to sort of give a sort of a roundup of what the state of RAS, KRAS specifically, research is looking like right now, which is bizarre.

blown up ever since uh durex on racib had the uh really great uh results so anyway i'm i'm getting too deep in but uh our story two was another really exciting clinical story um distarlamab uh which has was a huge story um a few years ago actually um it allows it's a checkpoint inhibitor that for uh certain locally advanced rectal cancer patients, it allows them to completely forego the standard of care, which is incredibly brutal.

And we see these targets are shared across tumor types.

For instance, KRAS is not just in pancreatic cancer.

KRAS is there in lung cancer, in breast cancer, in melanoma, in sarcoma, in many, many cancers.

So for the broad audience here, this is what is called tumor agnostic drug development or precision medicine-based drug development because we're used to thinking breast cancer, prostate cancer, lung cancer, kidney cancer.

A tumor agnostic way of thinking is doesn't matter what the tumor is.

Although we've had major, major headwinds in lung cancer, breast cancer, two cancers oncologists struggle is pancreatic cancer and glioblastoma.

Most of the patients with pancreatic cancer do not survive beyond two, three years after diagnosis.

10, 15 years ago, when I was in training, we were taught that KRAS is undruggable, especially the KRAS G12DV that we see in pancreatic cancer.

Other pathways are driving the tumor.

Concurrent with that, the initial, the mutant KRAS programs were making their way through clinical development into the market.

The mutant inhibitors, the first generations.

And while they- KRAS and G12C, those small molecules- Yeah, and while they were remarkably beneficial and obviously very targeted, what we saw was emergence evolved quickly.

And the emergence was all, again, from other pathways activating.

So, you're right, cancer cells evolve quickly.

We've known this forever, but we're sitting there watching this in our own hands and watching the KRAS programs.

So, we sat and thought about, like, could we develop a... a hetero-bifunctional induced proximity concept that's not degradation because we had done that and we thought the degradation field was well underway.

Five years later, she developed a recurrence and underwent secondary cytoreduction, followed by carboplatin and paclitaxel chemotherapy for six cycles and aromatase inhibitor maintenance.

Next-generation sequencing of the tumor at that time revealed a KRAS G12V mutation.

This patient had aromatase inhibitor maintenance for about three years, but unfortunately at that point was found to have a pelvic mass.

And although tertiary cytoreduction was considered, this mass was considered unresectable.

I think it was adjuvant therapy.

He actually had this patient seen by two gynecologic oncology specialists in Miami.

And they both, even though she was known to have a KRAS mutation all along, even back in Cuba, they both suggested hospice because the woman was in just very, very poor condition.

And the fiancé brought his patient home.

Five years later, she developed a recurrence and underwent secondary cytoreduction, followed by carboplatin and paclitaxel chemotherapy for six cycles and aromatase inhibitor maintenance.

Next-generation sequencing of the tumor at that time revealed a KRAS G12V mutation.

This patient had aromatase inhibitor maintenance for about three years, but unfortunately at that point was found to have a pelvic mass.

And although tertiary cytoreduction was considered, this mass was considered unresectable.

I think it was adjuvant therapy.

He actually had this patient seen by two gynecologic oncology specialists in Miami.

And they both, even though she was known to have a KRAS mutation all along, even back in Cuba, they both suggested hospice because the woman was in just very, very poor condition.

And the fiancé brought his patient home.