Two thousand years ago, all roads led to Rome. In the cell, all roads lead to survival. Its mission-critical roads are pathways marked by proteins working in an orderly sequence to enable the cell to grow, nourish itself, respond to threats, repair itself, and keep living. When the cell stops functioning at all or is too damaged to be repaired, another pathway eliminates the cell.
Cancer changes normal cellular processes. It alters, overtakes, or reroutes mission-critical survival pathways to make them do cancer’s bidding.
That’s why it’s so hard to treat.
The battle is on multiple fronts. Cancer can:
- Direct the body to create new blood vessels to feed the tumor
- Change hormone signaling
- Bypass needed DNA repairs
- Thwart the immune system’s defenses
Moreover, cancer has astonishing abilities to adapt. For example, it can pump anticancer agents out of the cells or find an alternate pathway to do its bidding when a drug blocks one path. And, when tumor cells are damaged, cancer can essentially run a light, telling cells to ignore the damage instead of repairing it. Damaged cells that keep dividing and making more tumor create progressively more damage—which creates more mutations. As cancer mutates further, it becomes harder to treat.
Cancer is a collection of diseases that reflect altered cellular characteristics. Mapping those alterations on a molecular level helps researchers find cancers’ weaknesses and create more effective, more precisely targeted treatments.
To fight cancer on multiple fronts, most regimens involve a combination of treatments: chemotherapy, immunotherapy, surgery, and/or radiation. The goal is to block more mission-critical paths at the same time, inflicting greater damage on cancer cells. But combination treatments damage more healthy cells, too—and can cause serious side effects. That’s why many patients can’t tolerate the full dose or full course of treatment. Instead of trying to address each pathway separately, a better option is to block cancer at a critical juncture that affects multiple pathways at the same time.
Clinically, that critical juncture is a signaling node—a particular protein that helps control activity for many pathways. That is the focus of Apexian’s work.
APE1/Ref-1 is a unique protein—a master traffic controller. Broadly, the protein performs two types of functions: repair and redox. The “APE1” functionality preps damaged DNA sites for repair. The “Ref-1” functionality keeps a diverse group of proteins called transcription factors in their active (“reduced”) state so they can bind to DNA. That binding action begins the process of making a variety of proteins for mission-critical functions (including growth).
Because the “Ref-1” side interacts with key proteins controlling multiple survival pathways (see table), it has wide-ranging effects on cellular health. That makes it a prime target for anticancer treatment. In many cancers, the “Ref-1” part of APE1/Ref-1 works overtime (is overexpressed). When that happens, tumors can grow faster, migrate more readily, and are less affected by drugs. Patients may not live as long when this protein is overexpressed.
If we could inhibit Ref-1 action, then cancers would be deprived of a key factor they need to run on multiple pathways.
Apexian has isolated the “Ref-1” from the “APE1” functions to create an inhibitor that affects only Ref-1 activity. The inhibitor, called APX3330, puts the brakes on multiple pathways that cancers rely on for survival. APX3330 is now in early clinical trials. Additional compounds are also in the Apexian pipeline.
|Pathway name||Normal functions||Cancer-induced functions||How Ref-1 inhibition affects this|
|STAT3||Promotes inflammation to kill foreign invaders||Increased cell growth, invasiveness||Reduces growth and tumor migration
Blocks STAT from being a cofactor for other key pathways—specifically, HIF-1 and NF-κB
|HIF-1||Counteracts low-oxygen cellular conditions that could hurt the cell||Increased cell growth, invasiveness, and survival||Decreases cell survival|
|CA9||Regulates intracellular pH||Acidifies the environment surrounding a tumor, which promotes cell survival and invasiveness||HIF-1 regulates CA9 and Ref-1 regulates HIF-1. So inhibiting HIF-1 also blocks CA9.|
|VEGF||Cell survival, growth and migration||Promotes growth of new blood vessels to nourish the tumor||HIF-1 regulates VEGF and Ref-1 regulates HIF-1. So inhibiting HIF-1 also blocks VEGF.|
|NF-κB||Promotes inflammation||Increased cell growth, migration, invasion, and survival||Decreases cell survival
Decreases the crosstalk between STAT3 and NF-κB pathways
|NOTE: These are the most-studied, primary pathways that Ref-1 inhibition affects. Lesser-studied pathways are not included in this list.