Bench to Bedside

With HR+ breast cancer alone accounting for some 70% of all breast cancer diagnoses, Sipkins’ discovery of the mechanisms by which these cancer cells get to into these pro-dormancy niches and how they might potentially be excised out before they can grow and multiply, is significant.

“At baseline, the sinusoids always look like inflamed blood vessels. And that’s what makes them special; that’s what allows tumor cells to dock there,” explained Sipkins. “What we think is that the breast cancer cells come in through the sinusoids, and they can hang out there for a long time doing nothing. Then, they migrate to these areas that are more removed from the sinusoids and closer to bone cells — an environment where they’re more likely to proliferate. The goal is to cut them off at the pass earlier in the disease; when they’re still hanging out in the sinusoids and haven’t yet got themselves up to no good.”

It’s impossible to predict, however, just when they might “get up to no good.”

“We have no clear understanding of why these dormant cells wake up and start growing,” said Marcom, noting that these breast cancer cells could lie dormant for five, 10, 20 or more years, with the longest he’s seen, 35 years. “In the early 1990’s, the ‘angiogenic switch' was all the rage and that is likely part of the explanation. However, given what we know now, the mechanism is clearly complex.  Another likely factor is that these dormant cancer cells are kept at bay by the effectiveness of the immune system until something changes and then they quickly grow some, get more genomic instability, then they take off. This is arguably the most important l final problem to be solved in treating breast cancer.”

Marcom, a medical oncologist who directs the Breast Cancer disease group, is encouraged by the possibilities of this new therapy.

“I haven’t been this excited about a new potential therapy since the CDK cell cycle inhibitors came along” he said. “It’s really a novel mechanism that addresses, no pun intended, a novel niche of therapy.”

Six patients with known HR+ breast cancer metastasis to the bone — stage 4 — will be enrolled for the single-site Phase 1b clinical trial of GMI-1359, to be held at Duke. Qualifying participants must be stable (or with slight progression) on anti-hormonal therapy as well as a CDK4/6-inhibitor (abemaciclib, palbociclib, or ribociclib) — the current standard-of-care therapy with for metastatic hormone driven breast cancer. 

Participants will receive increasing doses of the study agent once a month over approximately three months, then three successive daily doses at the highest tolerated dose.  While the primary focus of the trial is safety of the drug, the effects on normal blood cells, immune system markers, and cancer cell mobilization will also be analyzed. 

“This trial is going to be a proof of concept to see whether or not we see a bump in tumor cells circulating in the vasculature after a dose of the agent,” explained Sipkins. “We don’t know for sure, however, if we’ll have to see an elevation in the circulating tumor cells for this drug to be active in breast cancer patients. It’s possible that we’ll find that, even without having to leave the bone marrow, the inhibitor will render the cancer cells more sensitive to other treatments or put them in a more pro-apoptotic state.”

An exploratory objective of the trial will be examining how normal white blood cells in both the bone marrow and in circulation may change with this therapy.

If the study proves that the agent is safe, tolerable and there’s some signal that at the maximum dose that there are biomarkers to suggest the drug is hitting its targets (E-selectin and CXCR4), then a phase 2 trial in breast cancer may be the next step.

“Ultimately, the goal is to get this into early stage patients; patients who have finished conventional adjuvant treatment and are on endocrine therapy but for whom there’s evidence of residual tumor in the body; for example, a supersensitive circulating tumor cell DNA assay,” said Sipkins. “They’d then get treated with GMI-1359 in order to purge this micro metastatic disease. We’d also like to be able to use this once patients get to the metastatic setting where we treat them and try to control it.”

Sipkins’ office whiteboard is covered with formulas, drawings and equations. She said she can’t believe she’s been at this for nearly 30 years.

“As a physician scientist, you spend your life obsessing on this stuff and you hope that it has some relevance,” she said. “I hope this comes to something good.”