In the National Archaeological Museum of Lisbon, Portugal, a mummified middle-aged male of ancient Egypt is stored. Not long ago, scientists studied this corpse and found that there are many high-density round tumors between the pelvis and the lumbar spine, which is a typical manifestation of prostate cancer. Moreover, his prostate cancer has spread and spread throughout the body.
From ancient Egypt to the present, more than 2,000 years have passed. Today, prostate cancer is already one of the most common cancers in men, and one out of every nine men will develop prostate cancer in their lifetime. However, according to the authoritative report of the American Cancer Society, the mortality rate of prostate cancer patients in 2014 was sharply reduced by 51% compared with 1993. This reflects the tremendous progress of prostate cancer treatment in the past few decades. In today's article, the WuXi PharmaTech content team will work with readers to revisit the history of prostate cancer in humans.
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From the first prostate cancer to two Nobel Prizes
It is hard to imagine that prostate cancer was considered 'a very rare disease' when it was first diagnosed in 1853. In the next century, scientists and doctors have made very limited progress. In the 1940s, prostate cancer was synonymous with death. After diagnosis, the patient's survival time was only 1-2 years.
The transfer occurred in 1941. This year, Professor Charles Huggins of the University of Chicago and his colleagues published several papers revealing the relationship between hormones and the prostate. In theory, the growth and development of the prostate depends on the action of androgens. Therefore prostate cancer may also be associated with androgens. In other words, if it can inhibit the function of androgen, it may inhibit the growth of prostate cancer.
In this series of studies by Professor Huggins, scientists have confirmed that androgen and estrogen will compete and suppress each other. As they have previously envisaged, by injecting estrogen into patients, it can effectively delay the progression of prostate cancer. In addition, they also found that similar results can be achieved by surgical removal of the testes. Therefore, this practice of treating tumors by reducing androgen levels is also referred to as 'castration treatment.'
Many scientists believe that this is the first time humans have successfully controlled prostate cancer by using certain chemicals. Since the discovery of this hormone therapy, Professor Huggins also won the 1966 Nobel Prize in Physiology or Medicine.
Professor Huggins’s major discovery unveiled the curtain of endocrine therapy for prostate cancer. In the following decades, scientific breakthroughs have emerged, and a variety of drugs that inhibit androgen have also appeared. One of the important drivers came from the team of Professor Andrew Schally. Their research shows that a hypothalamic hormone called luteinizing hormone releasing hormone (LHRH) can ultimately promote testosterone production through a series of biochemical pathways, and testosterone is a major androgen. Based on this discovery, scientists have developed a drug called LHRH analog. In patients, high levels of LHRH analogues can inhibit testosterone production and also have therapeutic effects. As a result of the discovery of LHRH, Professor Sally shared the 1977 Nobel Prize in Physiology or Medicine with two other scientists.
Hormone therapy continues to break through bottlenecks
However, the road is one foot high and the height is one foot. Over time, people gradually discovered that after castration treatment, cancer cells will gradually adapt to this low hormone level environment and continue to grow. At this time, the disease also progressed to 'castration-resistant prostate cancer' (CRPC). Because prostate cancer has a long course, it is almost an inevitable stage of all prostate cancer, and the median survival of patients is only 1 to 2 years.
The presence of castration-resistant prostate cancer once puts endocrine therapy that inhibits androgen into a bottleneck, and treatment relies only on extremely limited means such as chemotherapy and radiation therapy. Until the new century, the relevant therapeutic field finally ushered in a new breakthrough.
One of the breakthroughs is 'anti-androgen therapy.' Unlike previous therapies, these therapies act directly on the androgen receptor, inhibiting androgen binding to it, and doing it more thoroughly. In fact, as early as 1989, the first generation of anti-androgen therapy factor was approved by the US FDA. However, early anti-androgens have a low affinity for androgen receptors, thus limiting the use of such therapies.
In 2012, Xtandi (enzalutamide), jointly developed by Medivation (later acquired by Pfizer) and Astellas, was approved for marketing. As a new generation of anti-androgen therapy, it inhibits both androgen binding to its receptors and inhibits androgen receptors from entering the nucleus, preventing it from initiating downstream biochemical pathways. In patients who suffer from castration-resistant prostate cancer and whose condition has metastasized and chemotherapy is powerless, half of the patients can survive for 18.4 months if they receive Xtandi treatment. This number was nearly five months longer than the placebo control group.
In 2018 and 2019, Janssen's Erleada (apalutamide) and Bayer's Nubeqa (darolutamide) were also approved by the FDA for listing in the army of castration-resistant prostate cancer.
It is worth mentioning that, just in September this year, Erleada was also approved to treat castration-sensitive prostate cancer, further expanding the number of people who can benefit. In clinical trials, it significantly prolonged the overall survival of patients and reduced the risk of death by 33%. Xtandi also reached the end of the extended overall survival in clinical trials for hormone-sensitive prostate cancer, and is expected to be approved by the end of this year.
At present, China's second-generation anti-androgen drugs from three pharmaceutical companies have entered Phase III clinical trials, including SHR3680 from Hengrui Medicine, Pukrudamide from Pioneer Pharmaceuticals, and HC-1119 from Sea Cisco.
In addition to the second-generation antiandrogens, there is the new hormonal therapy of Zytiga (abiraterone) approved by the FDA in 2011. Although it can also inhibit androgen, the principle is not to provide a relatively resistant hormone, nor directly against its receptor. Instead, it targets a key enzyme in the androgen synthesis pathway, CYP17.
As a highly potent, selective and irreversible CYP17 enzyme inhibitor, Zytiga blocks the synthesis of androgen in testes, adrenal glands, and prostate cancer tissues, minimizing androgen levels in the body. In a large phase 3 clinical trial involving 1,195 patients, its efficacy was also confirmed.
Expansion of the 'weapon bank': diversified treatment methods
Although hormone therapy continues to break through, it has always relied on the inhibition of androgen receptor signaling pathways to curb the proliferation of cancer cells. However, cancer cells eventually develop resistance to hormone therapy in a variety of ways. As a result, researchers are also developing innovative treatments that are not based on androgen signaling pathways, adding a diverse range of weapons to the arsenal of prostate cancer.
One of the innovative therapies is the world's first 'therapeutic' tumor vaccine Provenge (sipuleucel-T). As an individualized therapy, it separates dendritic cells (an antibody-presenting cell) from the patient's blood and co-cultures with a specific fusion protein. The fusion protein is divided into two parts, one is prostatic acid phosphatase (PAP), which is the main antigen on prostate cancer cells; the other is an immune signaling factor that promotes the maturity of these antibody-presenting cells. Subsequently, these processed cells, which are able to effectively recognize prostate cancer antigens, are returned to the patient and activate immune T cells to find and kill cancer cells that express PAP. Phase 3 clinical trial results also confirmed that it can significantly improve the median survival of patients.
Fortunately, a recent study found that these immune cells activated by tumor vaccines have long-term memory and are expected to have long-term therapeutic effects.
In addition, Merck's star immunotherapy Keytruda (pembrolizumab) has also achieved positive results in early clinical trials and has added three phase 3 clinical trials. In the future, it is also expected to bring good news to patients with prostate cancer.
In addition to the immunotherapy described above, targeted therapies developed based on the molecular characteristics of cancer have also become the latest trend in cancer treatment. In prostate cancer, the latest breakthrough comes from the use of PARP inhibitors. For example, in August this year, Merck (MSD) and AstraZeneca announced that Lynparza (olaparib) has achieved positive results in a phase III clinical trial of men with metastatic castration-resistant prostate cancer (mCRPC). Homologous recombination repair gene mutation (HRRm) and previous disease progression after hormone anticancer therapy (such as enzalutamide and abiraterone).
Future directions: prevention and new therapies will build a strong line of defense
At the same time that prostate cancer therapy has made a series of breakthroughs, the diagnosis of prostate cancer has also made important breakthroughs. Currently, a protein called prostate specific antigen (PSA) has been validated for decades, and can be used for early screening, adjuvant diagnosis, therapeutic monitoring, and prognosis of prostate cancer. Recently, a 13-year follow-up of the Lancet showed that PSA screening reduced prostate cancer mortality by 21% in men aged 55-69, and compared with 9 and 11 years of follow-up. This benefit is growing. This also confirms the importance of early screening for prostate cancer.
At present, although the incidence of prostate cancer remains high, it also reflects the progress of diagnostic screening technology to a certain extent. Under a range of available therapies, the patient's disease is well controlled and treated. The diagnosis of prostate cancer is no longer tantamount to leaving the world in the short term.
In the face of these advances, scientists have not stopped the pace of research and development, whether in the early screening of patients or the development of innovative therapies have made positive progress. For example, Bio-Techne's liquid-based biopsy test based on exosomes has recently received a breakthrough medical device certification from the US FDA. It allows prostate cancer patients to determine the type of prostate cancer without having to undergo an invasive tissue biopsy.
In the development of innovative therapies, Janssen recently announced that the PARP inhibitor nilapali has received FDA breakthrough therapy for the treatment of castration-resistant prostate cancer patients. In May of this year, WuXi PharmaTech partner Arvinas announced that its leading PROTAC protein degradation therapy ARV-110 was awarded the fast track qualification granted by the US FDA. ARV-110 directly degrades androgen receptors, which can be effective in cancer patients who over-express or produce mutations in androgen receptors, thereby benefiting mCRPC patients who are less responsive to second-generation hormone therapy. The therapy has now entered clinical trials and preliminary data is expected to be released later this year.
With the emergence of early screening techniques and innovative therapies, can humans eradicate prostate cancer, a killer that has plagued men for thousands of years? Let us wait and see!
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