Why prostate cancer treatment falls short

ManWithDoctor_InquiryBlog

A common treatment for prostate cancer targets only one type of cancer cell, leaving patients vulnerable to a second type that continues to multiply, according to work at the University of Minnesota and Minneapolis Veterans Affairs Medical Center (VAMC).

“The problem is that some of the cancer cells are dependent on androgens–testosterone and other male hormones–and some cancer cells require estrogens,” says research leader Akhouri Sinha, a professor in the Department of Genetics, Cell Biology and Development, the Masonic Cancer Center, and the VAMC. “[A common treatment] is to drastically reduce the supply of androgens, but that leaves the estrogen-dependent cancer cells to grow and thrive.

“It’s like trying to shut off a river by damming only the main channel, while letting water in the side channels continue to flow.”

Sinha advocates new research to find means of shutting off the production of estrogens and the steroid molecules from which they are made. The work is published in Anticancer Research.

When drastic treatment fails

Prostate cancer is the second most common solid organ tumor diagnosed in U.S. men. In 2015 an estimated 220,000 new cases and 27,000 deaths were attributed to the disease, according to the researchers.

Some 80 to 90 percent of tumors are classified as androgen-dependent at diagnosis. For those patients, the primary treatment is androgen deprivation therapy (ADT), which usually takes the form of “chemical castration” by drugs that inhibit the production of androgens. Often, however, the cancer stops responding, resulting in “castration-resistant prostate cancer” and a life expectancy of less than five years.

Sinha notes that as men age, their estrogen levels (relative to androgen levels) increase. Also, their risk of estrogen-dependent prostate cancer rises; this cancer is castration resistant.

“The risk of prostate cancer increases with each decade of aging, but varies depending on race and ethnicity,” Sinha says. “Starting at about 30 years of age, testosterone gradually declines each year. It reaches about 50 percent of the starting level in men over 50 years of age. This alters the relationship between androgen and estrogen levels, creating a hormonal imbalance at about age 50, the purported age of prostate cancer origin.”

Cancer cells speak

Nearly 40 years ago, Sinha and colleagues identified two kinds of basal cells in prostate tumors: androgen-dependent, which were killed by ADT; and androgen-independent, which tended to survive ADT. In the current study, they discovered that the androgen-independent cells were estrogen-dependent.

Using specialized staining techniques and microscopic examination, they found that the cancer cells had structures—called androgen receptors or estrogen receptors—on their outer membranes that allowed them to respond to the class of hormones on which they depended. The receptors acted as labels for the two cell types.

Untreated tumor tissue had a mix of androgen- and estrogen-dependent cells. In ADT-treated tissue, the androgen-dependent cells were disproportionately destroyed, while the estrogen-dependent cells persisted and multiplied. As ADT stretched from 37 days to 18 years, this trend continued. That should be no surprise, as ADT treatment will not destroy estrogen-dependent cells.

“My premise was that we have been treating prostate cancer with castration or ADT for 125 years, and it has not cured any of it,” Sinha says. “This may be one of the main reasons that ADT does not cure castration-resistant prostate cancer—estrogen-dependent cancer cells are the likely drivers of it.”

To combat this phenomenon, Sinha recommends research leading to therapy that will halt the production of estrogen as well as androgen, and also inhibit certain enzymes involved in the synthesis of steroids, the class of compounds to which both androgens and estrogens belong.

“Tamoxifen, which inhibits estrogen synthesis, is a possibility,” he says.

He also notes that in breast, uterine and cervical cancers, each type of cancer is regulated by specific organ-related steroid hormones and their receptors, which in turn are modulated by the menstrual cycle, pregnancy, menopause, and so on. These relationships are poorly understood. Sinha advocates studies to determine the specific hormonal requirements of these cancer cells so that treatment of female cancers, too, will no longer be “hit and miss.”