Straight Dope on Medicine: STING

Just a castaway, an island lost at sea, oh 

Another lonely day, with no one here but me, oh

More loneliness than any man could bear

Rescue me before I fall into despair, oh

I'll send an S.O.S to the world

I'll send an S.O.S to the world

I hope that someone gets my

I hope that someone gets my

I hope that someone gets my

Message in a bottle, yeah

Message in a bottle, yeah

                                          -Sting

Sting sings for rescue. In grandiloquent style. Unbeknownst to him, he may just deliver it. Such a reversal might be entirely lost on him. After all, he is a musician, and STING is stimulator of interferon genes. 

But, before we delve into the science, we should check out what the Bible has to say on the subject.

My father imposed heavy demands on you; I will make them even heavier. My father punished you with ordinary whips; I will punish you with whips that really sting your flesh.'"

Eventually it will bite like a snake and sting like a serpent.

Why must I continually suffer such painful anguish? Why must I endure the sting of their insults like an incurable wound? Will you let me down when I need you like a brook one goes to for water, but that cannot be relied on?"

O death, where is thy sting? O grave, where is thy victory?

Here, we are focusing on removing the sting of cancer, namely solid tumors.  They are among the most intractable types of cancer, for they are notoriously hard to penetrate with therapeutics. Eventually PsiOxus will get something out the door.

Along the way, we hope to stave off death and debilitation.

It would seem the right thing to do. 

What is a solid tumor?

That means the tumor doesn't contain any liquid or cysts.

Solid tumors can occur in several places. They include:

• Bones

• Muscles

• Organs

Not all tumors are cancerous. A tumor that does not have any cancer cells is called benign. A tumor with cancer cells is called malignant.

Doctors divide cancer into two main types: solid tumor cancers and cancers of the blood. Cancers of the blood are also called hematological cancers. Cancers in the blood don't form tumors.

Major types of solid tumors

Two major types of solid tumors are sarcomas and carcinomas. Many solid tumors, whether a sarcoma or a carcinoma, are often treated with surgery.

1. Sarcomas are tumors in a blood vessel, bone, fat tissue, ligament, lymph vessel, muscle or tendon. There are many types of sarcomas. They include: Ewing sarcoma and osteosarcoma, which are bone cancer sarcomas. Rhabdomyosarcoma, which is a soft tissue sarcoma found in muscles.

2. Carcinomas are tumors that form in epithelial cells. Epithelial cells are found in the skin, glands and the linings of organs. Those organs includes the bladder, ureters and part of the kidneys. One common carcinoma is adrenocortical carcinoma. This is when a tumor develops in one or both adrenal glands, located above each kidney.[i]

And yet, researchers in this field are not reticent about going against advanced solid tumors with STING. They have high hopes.

What are advanced solid tumors? Definition. A malignant solid neoplasm that has spread extensively to other anatomic sites or is no longer responding to treatment. [ from NCI]

Now, if your oncologist is worth his salt, he won't be stuck in the past where the prevailing solid tumor profiling was simply morphology (what the tumor looked like, shape, etc). This is too simplistic, and doesn't provide the best shot on goal. 

The advent of molecular profiling overcame the limitations of traditional solid tumor classification methods, which relied on the morphology of tumor cells and the surrounding tissue. Today, molecular profiling is a standard technique for classifying solid tumors, with established guidelines from the College of American Pathologists (CAP) and the European Society for Molecular Oncology (ESMO).

Everyone has signed off on it.

In turn, genomic technology has evolved to meet molecular profiling needs. Next-generation sequencing (NGS) provides a comprehensive method for assessing the majority of genes associated with solid tumors, including lung, colon, breast, melanoma, gastric, and ovarian cancers. NGS also delivers high sensitivity to capture tumor heterogeneity, which other approaches such as Sanger sequencing often miss.[ii]

The problem being that deploying STING alone just doesn't cut it. STING's forte is not a solo artist. 

While STING agonists have shown promise in preclinical research as mono- and adjunctive therapies—enough promise that companies like GSK have inked big deals to develop them—they’ve faltered when it’s time to translate them to the clinic.

Activating the STING protein triggered the release of IL-35-positive regulatory B cells. To their surprise, that process reduced the proliferation of natural killer cells, which are key to the immune system’s anti-tumor response. 

From this finding, they learned that they had to put the damper on the deleterious effect unleashing STING had. An IL-35 blocker would do. 

Combining IL-35-blocking antibodies with STING agonists reduced tumor growth more substantially than did treatment with either therapy on its own.

Unshackled from its shadow, STING went to work. 

The researchers started with animal models of pancreatic cancer, then expanded their study to include melanoma, triple-negative breast cancer and lung cancer. Their results were consistent across all tumor types and with five different types of STING agonists. The team has now submitted a patent application for the combined therapy and are gearing up to study it in humans.

Others wanted to get in on the excitement.

But the combo is key.

This spring, another research team led by scientists at UC Berkeley found that combining a STING agonist with an IL-2 superkine could “effectively cure” some subtypes of solid tumors.

Remarkably, in a primary autochthonous sarcoma model that is refractory to PD-1 checkpoint therapy, the combination of CDN/H9-MSA with checkpoint therapy yielded long-term remissions in the majority of the animals, mediated by T cells and NK cells. This combination therapy has the potential to activate responses in tumors resistant to current therapies and prevent MHC I loss accompanying acquired resistance of tumors to checkpoint therapy.

Scientists aren't done though. They are looking to pair STING up with other agents to further its prospects.

much of the excitement around them has come from their use with other treatment modalities, such as checkpoint blockade inhibitors. They’ve even been evaluted as an adjunct therapy with CAR-T cells by another team out of UNC.

It might seem that my newsletter topic selection is random. If so, I've achieved my goal. Yet, randomness doesn't render it unreasonable. To that end, the last video reflects the strategy in visual splendor.

References

[i] https://www.stjude.org/treatment/disease/solid-tumors/what-is-solid-tumor.html

[ii] https://www.illumina.com/areas-of-interest/cancer/clinical-cancer-research/somatic-mutations/solid-tumors.html

Wolf NK, Blaj C, Picton LK, Snyder G, Zhang L, Nicolai CJ, Ndubaku CO, McWhirter SM, Garcia KC, Raulet DH. Synergy of a STING agonist and an IL-2 superkine in cancer immunotherapy against MHC I-deficient and MHC I+ tumors. Proc Natl Acad Sci U S A. 2022 May 31;119(22)