U.S. Department of Defense supports dedicated program to more precisely match medicines against prostate cancer

Timed to coincide with Movember Men’s Health Awareness Month, celebrated annually in November, the three project partners — the University of Washington, Spanish National Cancer Research Centre (CNIO, Madrid), and Vall d´Hebron Institute of Oncology (VHIO) — announced that the U.S. Department of Defense (DoD) has backed a their proposed study aimed at advancing precision medicine against metastatic prostate cancer (mPC).

This joint three-year project will be fueled by one of DoD’s prestigious Impact Awards valued at US$2 million. The project leaders are Joaquin Mateo, Principal Investigator of VHIO’s Prostate Cancer Translational Research; David Olmos, Head of the CNIO’s Prostate Cancer Clinical Research Unit; and Colin C. Pritchard, Associate Director of the Genetics and Solid Tumors Laboratory at the University of Washington, USA.

Aimed at describing novel predictive markers to precisely gauge response in patients to standard therapies, this ambitious project also seeks to provide fresh hope to patients suffering with advanced prostate cancer by offering them alternative, tailored and more effective treatment strategies.

According to the latest global cancer data*, the worldwide cancer burden is estimated to rise to 18.1 million new cases and 9.6 million cancer deaths in 2018. Prostate cancer is the fourth mostly commonly diagnosed cancer, with an estimated 1.3 million new cases in 2018. While survival rates are rising, thanks in part to early diagnosis, this tumor type still remains the third most common cause of death in men across Europe.

Advanced prostate cancer is typically treated by hormone therapy, but some patients ultimately become resistant to treatment, with 90% developing metastasis. In these cases, cancers typically spread to the bones or lymph nodes, and sometimes also invade the liver and lungs. The average survival of individuals with metastatic prostate cancer (mPC) is around two years from diagnosis; there is currently no cure for advanced disease.

While an estimated one third of these patients respond poorly to available treatments, there is no current strategy to accurately predict response to therapy. Until now.

Impact Award

Thanks to the DoD Impact Award, Principal Investigators Mateo, Olmos, and Pritchard will aim to predict which patients are most likely to respond poorly to current therapies and provide an alternative, more effective therapy. They will identify new predictive biomarkers and undertake a clinical trial to assess the performance of a DNA damaging platinum chemotherapy, carboplatin, that is already used to treat other tumor types including ovarian and breast cancer.

Between 20-25% of all mPC patients undergo mutations in the genes responsible for maintaining the integrity of DNA in cancer cells. To test whether these switches are responsible for the varying responses of individual patients to current therapies, the researchers will study the molecular defects associated with damage to DNA repair mechanisms. “Our group’s research has long since centered on these mechanisms since they are clearly helping us to advance insights into metastatic prostate cancer,” observed Elena Castro, Clinical Investigator of CNIO’s Prostate Cancer Clinical Research Unit.

The team will also assess whether their identified subpopulation of patients responds to carboplatin therapy. “Carboplatin therapy blocks cells from repairing DNA damage. Given that cancer cells have many more genetic defects than normal ones, this agent is extremely effective in triggering their demise,” said CNIO’s David Olmos.

The researchers will perform targeted DNA sequencing studies on tumor samples from the 419 patients who participated in the PROREPAIR-B observational study in order to correlate certain DNA mutations with patient outcomes and guide optimal therapeutic strategies. PROREPAIR-B, coordinated by CNIO since 2013, is the first prospective clinical trial for patients with advanced prostate cancer with inherited gene mutations. (It was designed to establish whether the DNA damage repair genes of these patients have inherited alterations and how these might affect response to therapy. The researchers will now seek to confirm how alterations that are not caused by inherited mutations and only occur in the tumor, behave.)

Joaquin Mateo’s team will search for DNA damage and repair biomarkers in these patients, as these deficiencies do not always originate from an inherited mutation. “In recent years, we have shown that a significant number of patients with metastatic prostate cancer develop defects in DNA repair without the presence of an inherited mutation,” explained Joaquin Mateo, PI of VHIO´s Prostate Cancer Translational Research Group and Medical Oncologist of VHIO’s Genitourinary, CNS Tumors, Sarcoma & Cancer of Unknown Primary Site Group, directed by Joan Carles.

“We also know that some tumors behave similarly to those with these mutations, although they have not yet been identified. Our research will focus on biological parameters with clinical value by studying these tumors using a range of tools and techniques in the lab,” he added. The objective is to count on these new signals as indicators of damage — more so than genetic mutations — that will guide and accelerate more precise treatment decisions.

Finally, CNIO, in collaboration with VHIO and other research centers across Spain, will conduct a clinical trial to establish whether carboplatin-based therapy might be effective for the treatment of patients with advanced prostate cancer. “Carboplatin performs well against DNA repair defects in patients with breast and ovarian cancer, and we hypothesize that it will work just as effectively in treating our subpopulation of patients,” said Olmos.

He continued, “Instead of selecting patients based on genetic mutations that could trigger DNA repair defects, we will be guided using previously defined biomarkers. We believe this to be a better approach in more precisely selecting therapies matched to the specificities of each patient’s tumor. In short, we will select patients on the basis of whether their tumor repairs DNA or not, irrespective of genetic profile.”

Carboplatin is less expensive than its counterparts, including an array of PARP inhibitors. “If carboplatin proves effective in the treatment of our patients, our results could represent a crucial next step in improving outcomes for individuals diagnosed with metastatic prostate cancer,” added Olmos.

Mateo concluded, “This therapy has already been approved and is used routinely to treat patients with other tumor types including breast and ovarian cancers. This means that carboplatin could be rapidly applied to the clinic for the treatment of patients with mPC. We are now striving to translate promising into proven.”

Reference:

*The GLOBOCAN 2018 database, International Agency for Research on Cancer (IARC) Global Cancer Observatory: http://gco.iarc.fr/.

Image: Prostate cancer sample with loss of two copies of the BRCA2 gene. BRCA2, also implicated in breast and ovarian cancers, is involved in DNA repair more commonly altered in prostate cancer. /CNIO