Myc

And clearly, the activated B-cell subset, you know, cluster 5, the MCD, these are the patients who have a lot of extranodal disease, testicular CNS involvement.

really do seem to derive the greatest benefit from Pola Archip, but because the study wasn't designed in that way and the toxicity is relatively similar, I think most of us in our practice would use it as it was in the study with an IPIF2 or higher, knowing that some patients who are germinal center subtype may be what's called the dark zone signature, and those are a very aggressive subtype that are MYC-driven.

We don't test for that, so we sort of just extrapolate, though I know other places where people really use this.

If it's a germinal center, CD10 positive, they give, you know, RCHOP, which I think is not unreasonable.

I'll also just mention a few, uh, novel targets that are being explored.

So this past ASH and ASCO, we saw data on a drug called enobradib, which is a, a first in class inhibitor of the P300 CBP pathway that is involved in activation of oncogenic pathways like, uh, MYC or IRF4.

And there's a phase two study called the DOMINO trial that's examining enobradib with pomalidomide dexamethasone in relapse refractory myeloma.

Another agent is called cemsitamide that works similar to the CELMoDs and activates, uh, cereblon to degrade certain pro-survival factors such as IKoro or NALOS, and is being studied in a, a phase two study called MOMENTUM with dexamethasone relapse myeloma.

You are deliberately walking the cell right up to the edge of the pluripotency cliff, pausing to clean the software, and pulling it back before it forgets its identity.

But, and this is a big but, what if that mechanical switch is leaky? Because if dropping MYC lowers the immediate cancer risk, the long-term safety relies totally on that doxycycline promoter being airtight.

Yes, it absolutely does.

What happens if a patient gets this therapy in their eye? Everything goes dormant.

If you see something described as colloquially a triple-hit or a double-hit lymphoma, that means they have two of the three high-grade mutations that we see associated with the large-cell lymphomas.

That is a MYC rearrangement and one or both of a BCL2 and BCL6 mutation to make yourself either a triple, or if you have all of them, or a double-hit if you have one of them respectively.

Don't worry if none of this makes any sense at all.

We will talk more in the DLBCL episode on the difference between a lymphoma that expresses one of these markers by IHC or having a genetic mutation detectable by fish and how the combinations work.

Interesting.

I mean, speaking of some translocations, for instance, we can find the translocation 1418 that switches BCL2 into overdrive and follicular lymphoma.

We can find the translocation 1114, which drives signaling D1 in mantle cell, or the T814 MYC rearrangement of Burkitt's lymphoma.

You can think of these as fingerprints of their respective diseases.

markers, that's coming.

I remember when I was with John, and this goes back decades, MYC was a major issue in small cell lung cancer.

In non-small cell lung cancer, tell me about MYC and is MYC a target that may be a downstream of many of these other molecular mutations? So MYC

is by itself a driver.

It's often amplified in small cell lung cancer.

We've known about, as you know, Mick for many decades.

In fact, when I was a grad student, I was rotating in a lab, and my PI said, do you know what Mick stands for? I said, no, what? He says, man, you're crazy, because he was studying Mick.

So unfortunately today... we still don't have a way to directly target MYC.

Yes

... cMyc and, uh, Klf.

Right, those are the four Yamanaka factors.

Right.

Yeah, this is, um, what they're calling this is cellular rejuvenation.

Right.

Essentially, they took cMyc out, which was the most, uh, carcinogenic, or it's a known oncogene.

It can cause cancer.

Once the biopsy confirms D-LBCL, you need to determine what type of lymphoma you're dealing with because some subtypes require different treatment.

At a high yield level, remember three things, cell of origin, MYC-BCL, two abnormalities, and overall risk.

DLBCL can be broadly classified as germinal center B cell-like, or GCB, versus activated B cell-like, or ABC-slash-non-GCB.

ABC-slash-non-GCB disease generally has a worse prognosis with traditional therapy, although treatment decisions are increasingly based on the overall clinical and molecular picture.

The other major distinction is double-hit lymphoma.

This refers to rearrangements involving MYC and BCL2 and sometimes BCL6 depending on the classification.

These patients have particularly aggressive disease and generally require more intensive treatment than standard DLBCL.

Don't confuse this with double-expressor lymphoma.

It simply overwhelms the drug supply by sheer volume.

Alongside amplifying KRAS, the tumors were also found to amplify entirely different growth pathways, like MYC and receptor tyrosine kinases, or RTKs.

It's like we finally set up a perfect roadblock on the main highway so the tumor just instantly paves 10 new side roads to keep traffic moving.

Exactly.