Breast Cancer and RAD140: A Case Study Summary

RAD140

The American Cancer Society estimates that in 2022, around 287,850 women will receive a diagnosis of invasive breast cancer. That number feels startling; however, the good news is that there is ongoing research looking at new methods of treating breast cancer. 

One potential treatment for this devastating disease includes RAD140. Keep reading to learn more about the research being done with SARMs and breast cancer. 

RAD140 in Breast Cancer Models

This study from 2017, looked at the androgen receptor (AR) and estrogen receptor (ER) positive (AR/ER+) breast cancer cells. Because steroidal androgens had been successful in suppressing these cells, researchers wanted to determine if the oral selective androgen receptor modulator RAD140 would be effective as well. 

To determine this, they looked at both in vitro and in vivo models of androgen receptor and estrogen receptor-positive breast cancer. 

Methods

For the in vivo portion of this test, researchers used female athymic nude mice. They implanted tumor fragments subcutaneously in the flank. 

Researchers administered RAD140, Dihydrotestosterone (DHT), or fulvestrant as a single agent or in combination with palbociclib to the mice. 

Researchers administered the RAD140, palbociclib, and the vehicle (0.5 percent carboxymethyl cellulose orally. The fulvestrant was administered as a subcutaneous injection, and the DHT was given as subcutaneously implanted pellets. 

This occurred from the day of randomization to the end of treatment, and body weight, and tumor volume measurements occurred two times per week. 

For the in vitro study, well plates were used. The cells were seeded in medium with 10 percent CSS at 30,000 cells per well in 24 well plates. 

These were then treated for fourteen days with RAD140, DHR, or DMSO. The treatments were renewed every three days. 

At the end of the fourteen-day treatment period, the trypsinized cells were stained with Trypan blue. Researchers used a Nexcelom Cellometer for live cell counting. 

Results and Conclusions

The results of this study showed that RAD140 is a powerful androgen receptor in breast cancer cells. It has a distinct mechanism of action; this includes the androgen receptor-mediated repression of ESR1. 

In addition, RAD140 inhibits the growth of multiple androgen receptor and estrogen receptor-positive breast cancer PDX models. It does this in combination with palbociclib and as a single agent. 

Because of the results of this study further clinical investigation of RAD140 as a treatment for AR/ER+ breast cancer patients should be completed. 

RAD140 in Metastatic Breast Cancer

The following study we’ll look at published in January of 2022. This study was the first in human phase one study for using RAD140 in the treatment of ER+/HER2- metastatic breast cancer. 

The goal of this study was to assess the following from RAD140 treatment:

  • Safety
  • Tolerability
  • Antitumor activity
  • Maximum tolerated dose
  • Pharmacokinetic profile

Method

This study was a dose-escalation study. Researchers used a 3 + 3 design. The women enrolled were premenopausal and diagnosed with ER+ and human epidermal growth factor receptor 2 metastatic breast cancer. 

Researchers used serum sex hormone-binding globulin and a prostate-specific antigen as surrogate markers of AR engagement. 

Overall, 22 heavily pretreated women with metastatic breast cancer enrolled in the study. 

Women received their dosage once daily. The dose levels included

  • 50 mg (six women) 
  • 100 mg (13 women)
  • 150 mg (three women) 

Results and Conclusions

There were some treatment-emergent adverse events. The most frequent consisted of elevated: 

  • Aspartate Aminotransferase (59.1 percent) 
  • Alanine Transaminase (45.5 percent) 
  • Total blood bilirubin (27.3 percent) 

In addition, some participants experienced vomiting, decreased appetite, and weight (27.3 percent each). The half-life of 44.7 hours supported the once-a-day dosing. 

One patient receiving the 100 mg a day dosage had a partial response at baseline, this patient had an ESR1 mutation. Overall, at 24 weeks, the clinical benefit rate was 18.2 percent. 

The median progression-free survival for participants was 2.3 months. The paired baseline and on-treatment biopsies showed AR engagement with this treatment. 

Researchers determined that RAD140 has potential in treating AR+/ER+/HER2- metastatic breast cancer with an acceptable safety profile. 

RAD140 in ER+/HER2- Breast Cancer

This study was published in 2019 and looked at RAD140 in ER+/HER- breast cancer. Because the androgen receptor is expressed in about 90 percent of estrogen receptor-positive breast cancer. 

Therapies that are androgen-based have had response rates up to 20 to 25 percent. However, because of poor tissue selectivity, potential aromatization to estrogen, and the emergence of ER-targeted agents, these therapies aren’t in common use. 

Researchers used this phase one dose-escalation study to look at the nonsteroidal selective androgen receptor modulator (SARM) RAD140. 

Methods

Researchers used a 3 + 3 design for this study. Their primary objective was to determine the safety, and the maximum tolerated dose. Secondary objectives included pharmacokinetics and antitumor activity. 

The eligibility requirements for participants included the following:

  • ER+/HER2- and inoperable metastatic breast cancer
  • Post-menopausal
  • Ineligible for standard therapy

Androgen receptor engagement was assessed using sex hormone-binding globulin and serum prostate-specific antigen. The study included 16 participants. Dose levels were as follows: 

  • 50 mg (six participants) 
  • 100 mg (seven participants) 
  • 150 mg (three participants) 

Each participant was dosed daily, and the median amount of time for treatment was eight weeks. 

Results and Conclusions

The most frequent adverse events of this treatment include:

  • Elevated Aspartate Aminotransferase and Alanine Transaminase
  • Decreased appetite and weight 
  • Constipation

There were no deaths related to the drugs during the study. One participant receiving a dosage of 100 mg had a partial response. Two participants showed stable disease at greater than or equal to 12 weeks. 

It took 15.9 weeks to achieve a partial response. Sex hormone-binding globulin decreased in 12 out of 12 participants. While prostate-specific antigens increased in 10 out of 14 participants, including the participant with a partial response. 

Researchers concluded that the maximum tolerated dose for RAD140 is 100 mg once a day but that there is still a high risk of elevated liver enzymes. In addition, they determined that it has an acceptable safety profile for treatment of the disease and that there is preliminary evidence of antitumor activity and target engagement. 

Continued Need for Research With RAD140

There have been promising results, but at the same time, there is a continued need for research with RAD140. Are you preparing to do your own SARMs research? 

Contact Sports Technology Labs today to discuss your SARMs needs. 

Resources: 

Hamilton E, Vidula N, Ma C, LoRusso P, Bagley RG, Yu Z, Annett M, Weitzman A, Conlan MG, Weise A. Phase I dose escalation study of a selective androgen receptor modulator RAD140 in estrogen receptor positive (ER+), HER2 negative (HER2-) breast cancer (BC). Annals of Oncology. 2020 Jan 8 [accessed 2022 Apr 22]. https://www.sciencedirect.com/science/article/pii/S0923753419585659

LoRusso P, Hamilton E, Ma C, Vidula N, Bagley RG, Troy S, Annett M, Yu Z, Conlan MG, Weise A. A first-in-human phase 1 study of a novel selective androgen receptor modulator (SARM), RAD140, in er+/her2- metastatic breast cancer. Clinical Breast Cancer. 2021 Aug 20 [accessed 2022 Apr 22]. https://www.sciencedirect.com/science/article/abs/pii/S1526820921002408

Yu Z, He S, Wang D, Patel HK, Miller CP, Brown JL, Hattersley G, Saeh JC. Selective androgen receptor modulator RAD140 inhibits the growth of androgen/estrogen receptor–positive breast cancer models with a distinct mechanism of action. American Association for Cancer Research. 2017 Dec 14 [accessed 2022 Apr 22]. https://aacrjournals.org/clincancerres/article/23/24/7608/79963/Selective-Androgen-Receptor-Modulator-RAD140

Breast Cancer and RAD140: A Case Study Summary

Leave a Reply

Your email address will not be published.