Undone Proteins Take Out Bladder Cancer

An unfolded protein found in human milk shows promise in early clinical trials to treat bladder cancer.

Roni Dengler, PhD
Jul 20, 2021

A serendipitous discovery more than 25 years ago set Catharina Svanborg, an immunologist at Lund University in Sweden, on a rare path among biologists; she took a molecule all the way from its discovery to the bedside. 

While looking for antibacterial molecules in natural sources like blood, tears, or human milk, Svanborg and her team tested the antibiotic properties in cancer cells because they multiply and are easier to handle than non-cancer cells. When they added a certain fraction of human milk, the cancer cells died.1

“We repeated the experiment again the next day, and they still died, so we thought, ‘Oh, this must be interesting,’” Svanborg recalled. 

The molecule Svanborg and her team eventually identified in human milk, alpha-lactalbumin, holds a surprising property. Most proteins in the body must fold into a specific shape to carry out essential tasks such as digesting food and fighting off infections as antibodies. When they don’t, unfolded proteins can be toxic to cells. Yet, alpha-lactalbumin is a partially unfolded protein.

Now Svanborg and her colleagues have capitalized on this toxicity to take out tumor cells specifically, while leaving healthy cells alone. A Phase I/II clinical trial in patients with bladder cancer revealed a promising alternative to more toxic therapeutic options.

An unfolded protein found in human milk may lead to less toxic therapies for bladder cancer.
Dominika Roseclay

Alpha-lactalbumin is a whey protein that makes up nearly a quarter of the proteins in human milk.2 In the mammary gland, it takes on a precise and expected shape to help make lactose, a central milk sugar. But when in the presence of a specific fatty acid and partially unfolded—conditions that resemble the protein’s status in the human stomach—alpha-lactalbumin becomes something else entirely: alpha1-oleate. Svanborg and her colleagues dubbed this protein HAMLET, human alpha-lactalbumin made lethal to tumor cells.3

In previous research, the team showed that HAMLET is a potent cancer cell killer. When applied to warts, HAMLET resolved the growths, demonstrating that the molecule targets cancerous cells.4 HAMLET also reduced the size of tumors in rats modeling human brain cancer and extended the animals’ lives, suggesting anticancer activity.5 In a study published last year, Svanborg and colleagues demonstrated that a synthetic version of HAMLET treated bladder cancer in mice without toxic side effects.6

In the new research, Svanborg and her colleagues treated non-muscle invasive bladder cancer patients with the compound six times over a 22-day period. Half of the patients received a placebo solution identical in appearance to the treatment.

The treatment triggered massive tumor cell shedding and reduced tumor size, Svanborg and her team reported in Nature Communications.7 The researchers did not detect toxicity in healthy tissues from patients, who were free of adverse events, suggesting low drug toxicity.

“The patients responded to it beautifully,” Svanborg said. “It’s quite exciting and very promising.”

Ashish Kamat, a urologic oncologist at the MD Anderson Cancer Center who was not involved with the research, is cautiously optimistic about the results. “If it actually does continue to demonstrate activity in patients when done on a larger scale, and [with] a low toxicity, that's a big plus,” he said. “Most of the current therapies we have for our patients in bladder cancer, if they work, they also have a fair amount of toxicity attached to them. Some of them don't work, and still have toxicity, so to have something that is so low toxicity and has efficacy would be a win-win for the patients.”

Svanborg is more than cautiously optimistic. “There are no warning signs so far that we can’t go on and develop this into a proper drug,” she said. 

References:

  1. A, Håkansson et al., “Apoptosis induced by a human milk protein,” PNAS, 92(17):8064-68, 1995. 
  2. D.K. Layman et al., “Applications for α-lactalbumin in human nutrition,” Nutr Rev, 76(6):444-60, 2018.
  3. M. Svensson et al., “Conversion of α-lactalbumin to a protein inducing apoptosis,” PNAS, 97(8):4221-26, 2000.
  4. L. Gustafsson et al., “Treatment of skin papillomas with topical α-lactalbumin–oleic acid,” NEJM, 350(26):2663-72, 2004.
  5. W. Fischer et al., “Human alpha-lactalbumin made lethal to tumor cells (Hamlet) kills human glioblastoma cells in brain xenografts by an apoptosis-like mechanism and prolongs survival,” Cancer Res, 64(6):2105-12, 2004.
  6. T.T. Hien et al., “Bladder cancer therapy without toxicity—A dose-escalation study of alpha1-oleate,” Int JvCancer, 147(9):2479-92, 2020.
  7. A. Brisuda et al., “Bladder cancer therapy using a conformationally fluid tumoricidal peptide complex.” Nat Commun, 12(1):3427, 2021.