Antibodies and Small Molecules: Two Different Tools to Target PSMA

Prostate-specific membrane antigen (PSMA) is a molecular marker present on the surface of virtually all prostate cancer cells. It can be targeted by different molecular agents that bind to PSMA. This enables a targeted approach to find and image or treat prostate cancer cells wherever they are in the body, including the cells that have escaped (metastasized) to other organs.

The most commonly used agents to target PSMA fall into two categories: small molecules (also known as peptides, ligands, or inhibitors) or antibodies (also termed monoclonal antibodies).

Small molecule- and antibody-based molecules that bind to PSMA have different physical characteristics and these have implications on the way the molecules circulate through the body.

For example, peptides and other small molecules that target PSMA are much smaller than antibodies – approximately 100-fold smaller. As a result of their small size, peptides are able to quickly travel through blood vessels and disperse throughout all body tissues – both normal and tumor – and they are also rapidly excreted by the kidney into the urine and bladder.

Conversely, the larger antibodies tend to stay within the circulating blood and flow more selectively through the larger, abnormal blood vessels within tumors than the vessels in normal tissues. Their large size also prevents them from being excreted by the kidneys. Because of these properties, peptides can penetrate tumors, as well as normal tissues, rapidly and then disappear from the body quickly, in minutes to hours; antibodies take longer to travel and enter the tumor, but this is compensated for by the longer amount of time they spend in the body (days to weeks) and their decreased likelihood to penetrate into normal tissues.

Imaging

From a diagnostic imaging perspective, small molecules are typically better, as the rapid excretion of the radiolabeled peptide quickly minimizes the radioactive background “noise” seen on a scan. Additionally, using small molecules means that patients can be injected with imaging agents and then undergo scans quickly thereafter (on the same day within 1-3 hours). Physicians can see good contrast of the cancerous cells compared to other parts of the body with this method. In comparison, patients must return approximately 3-8 days after infusion with a monoclonal antibody for scans. Some of the benefit of using small molecules is offset by the fact that they are excreted via the urine and accumulate in the urinary bladder. This may lead to an intense signal in the urinary bladder area of the scan, adjacent to the prostate gland and lymph nodes in the pelvis, thereby possibly obscuring these potential sites of tumor. On the other hand, some antibodies are taken up by the liver, obscuring visualization of that organ. Antibody fragments such as so-called “mini-bodies” (derived from the whole antibody), are half the size of a normal antibody, but still large enough so as not to be excreted in the urine, and as such, they may provide improved imaging of the prostate and the pelvic area. This is currently under investigation at Weill Cornell Medicine and NewYork-Presbyterian Hospital.

The nuances of these molecular targeting agents aside, it is clear that both peptide-, antibody or mini-body-based agents provide significantly improved targeted molecular imaging of prostate cancer compared with conventional modalities such as bone, CT, and MR scans and also have some advantages over glucose (FDG), sodium fluoride (bone), choline, or fluciclovine (FACBC) PET scans.

Treatment

From a therapeutic perspective, there are theoretical advantages to the faster tumor penetration of the smaller molecule targeting agents, but this may be offset by their quick disappearance and their ability to impact normal tissue. The longer time antibodies spend circulating in the body theoretically provides for a greater amount of the treatment agent to get internalized into the cancer cells, allowing greater uptake of the payload agent (such as a radionuclide) that is being delivered to kill the cancer cells. Additionally, some antibodies may also be engineered to generate an immune response.

Does uptake in different body areas lead to side effects?

The different characteristics of small molecules and antibodies confer advantages and disadvantages when targeting PSMA on cancer cells within the body. Because of their small size, small molecules/peptides can penetrate through the depths of the tumor very quickly, but they also readily target normal tissues that express low levels of PSMA such as the salivary glands, small intestine, and kidneys. When using as a therapeutic delivery vehicle, this might lead to dry mouth, nausea, or delayed kidney damage. Luckily, no significant kidney damage has been seen in humans to date, but the number of patients treated on prospective clinical trials remains small and follow up is short. An antibody, on the other hand, does not target salivary glands or kidneys because its larger size leads to relatively restricted access to those normal sites. However, it circulates in the body for a longer period of time including high flow through the bone marrow. Antibodies tagged with radioactive particles may therefore contribute to non-specific side effects such as temporary decreased blood counts. This is a common (expected) toxicity related to the dose and schedule of the radiolabeled antibody.

Currently, it is not known whether peptide-based or antibody-based targeted PSMA prostate cancer treatments provide better results, but both approaches offer therapeutic benefit to patients. At Weill Cornell Medicine and NewYork-Presbyterian Hospital – where we have almost two decades of experience pioneering prostate cancer imaging and treatment with PSMA-targeted agents – we are the only center in the world currently able to offer both types of imaging and treatment modalities and plan to combine both within individual patients. We hypothesize that will be able to use the favorable properties of each targeting agent at slightly lower than maximal doses to deliver a higher amount of therapeutic payload to tumor with less to normal organs, further improving the tumor kill : side effect ratio and have initiated a clinical trial testing this approach.


References

Phase I Trial of 177lutetium-Labeled J591, a Monoclonal Antibody to Prostate-Specific Membrane Antigen, in Patients with Androgen-Independent Prostate Cancer

Phase II Study of Lutetium-177-Labeled Anti-Prostate-Specific Membrane Antigen Monoclonal Antibody J591 for Metastatic Castration-Resistant Prostate Cancer 

 

Prevalence and Clinical Outcomes of Advanced Prostate Cancer Patients with Inherited DNA-Repair Mutations

DNA Helix_NCICollaborative work has shown that approximately 12% of men with advanced prostate cancer have inherited, or germline, DNA-repair mutations that disrupt the normal function of the genes involved in repairing damaged DNA. Somatic alterations in DNA-repair pathways are also common in prostate cancer, particularly in late-stage disease. Somatic alterations affect only tumor cells, but are not inherited or passed on. Inherited mutations in DNA-repair genes – such as BRCA2, ATM, and CHEK2 – are associated with an increased risk of several other cancers as well as prostate cancer, including breast, ovarian, and pancreatic cancer. In particular, mutations in BRCA2, associated with 1.8% of overall prostate cancer cases, have been associated with more aggressive prostate cancer characteristics and worse outcomes, including increased risk of recurrence and poorer overall survival rates.

As a result of the increasing number of men with these types of mutations, the National Comprehensive Cancer Network (NCCN) guidelines have recently changed, now recommending genetic testing for all men with metastatic prostate cancer.

Weill Cornell Medicine

“Genetic testing for inherited mutations may provide some men with prognostic information about their prostate cancer risk,” says Dr. Scott Tagawa, Director of the Weill Cornell Medicine and NewYork-Presbyterian Genitourinary (GU) Oncology Program. “Even more importantly, genetic testing can also be used to inform screening of family members and may increasingly inform precision-medicine based approaches to manage the disease using specific molecular features such as DNA-repair genes,” says Dr. Tagawa.

How do Inherited Mutations Impact Treatment?

Clinical research studies are continually being conducted to investigate new ways to treat advanced prostate cancer patients with germline DNA-repair mutations since these patients comprise a unique subset of patients. Currently, little has been known about whether DNA-repair mutation status impacts benefit from standard therapies for the disease and this is just one area that needs to be researched in order to specifically tailor treatment options for this subset of patients.

Weill Cornell Medicine and NewYork-Presbyterian’s Drs. Himisha Beltran, Scott Tagawa and David Nanus, along with collaborators from around the globe, address this in research published today in the high impact factor journal European Urology and simultaneously presented at the American Society of Oncology (ASCO) 2018 Genitourinary (GU) Cancers Symposium by Dr. Misha Beltran. The researchers reviewed 390 medical records of patients who previously participated in a New England Journal of Medicine (NEJM) study examining men with advanced prostate cancer with known germline DNA-repair mutations and those without these mutations. The goal of the research was to determine whether germline mutations in DNA-repair genes impact the benefit of standard therapies for metastatic prostate cancer, such as docetaxel chemotherapy and androgen receptor signaling inhibitors abiraterone acetate and enzalutamide. Results showed that all patients appeared to benefit from standard therapies similarly to other metastatic prostate cancer patients, regardless of germline mutation status.

“The data suggest that metastatic prostate cancer patients with inherited mutations in DNA damage repair genes, including those with BRCA2 mutation, derive similar benefit from standard of care therapies in terms of both response rate and progression-free survival,” says Dr. Scott Tagawa. “While we continue to investigate additional agents thought to preferentially benefit those with DNA repair alterations, current evidence indicates that detection of any of these mutations should not prevent metastatic prostate cancer patients from receiving standard therapies including taxanes, abiraterone and enzalutamide, as standard of care treatment.”

Additionally, sophisticated genetic analysis and testing may be performed by genetic counselors and widely-available commercial testing is also available to physicians and patients. Dr. Panagiotis Vlachostergios, fellow and medical oncologist at Weill Cornell Medicine and NewYork-Presbyterian, presented research at ASCO Genitourinary (GU) Cancers Symposium focused on using a commercial 30-gene panel to test men with localized prostate cancer and advanced prostate cancer for the presence of inherited gene mutations. Out of the 17 men with localized disease and 35 men with metastatic prostate cancer, eight of 52 (15%) were found to have a germline alteration. A higher percentage of men with an inherited mutation had localized (23.5%) versus advanced disease (11.4%), though testing might have been biased towards those with family history of cancer or those diagnosed with high-grade cancer at earlier age.

Both the results published in European Urology and research presented at the 2018 ASCO GU Cancer Symposium underscore the importance of genetic testing to determine what, if any, mutations may be present in prostate cancer in order to determine the best possible treatment options. While the published data supports the use of standard therapies in those with metastatic prostate cancer who have germline DNA-repair mutations, not all patients respond to these types of treatment, demonstrating the need for alternate treatment options for this patient population. Weill Cornell Medicine and NewYork-Presbyterian are in the process of opening several clinical trials to include men with prostate cancer in need of different lines of therapy. Clinical trials testing PARP inhibitors, a drug target for cancer therapy that appears to be more effective in prostate cancer patients with DNA-repair mutations, are ongoing and may offer additional therapy options for this group of patients in the near future.

Movember 2017 is Here!

For nearly 10 years, we have been proud to participate in a month-long campaign to raise awareness and funds for men’s health each November, also known as Movember.

The campaign dates back to 2003 when two friends in Australia tried to bring back the moustache trend by growing out moustaches (or “mo’s” as they are commonly called in Australia) during the month of November. The following year, after realizing that this facial hair served as a conversation-starter, they decided to channel that energy to raise money for prostate cancer research.

Awareness (and mustaches) have grown over the years, and in 2007, Movember officially launched a global campaign to change the face of men’s health – literally and figuratively through increased awareness and funds. Another way people can get involved is by “moving” and setting a walking, running, biking or swimming goal and working to achieve it every day throughout Movember. Today, over 5 million people from more than 20 countries have collectively raised over $700 million dollars. The Movember Foundation uses this money to fund research around the world to reduce the number of men dying from prostate and testicular cancer, as well as mental health issues. Movember is committed to funding research that will reduce the number of deaths from prostate and testicular cancer by 50% by 2030.

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From L to R: Dr. Scott Tagawa, last year’s Movember Captain, Dr. Daniel Margolis, this year’s Movember captain

We’ve been proud Movember partners for nearly 10 years now and have benefitted from many Movember research grants to further our cancer research, most recently being named one of six teams to receive a 2017 Challenge Award from the Prostate Cancer Foundation (PCF) and the Movember Foundation to investigate new, cutting-edge treatments for metastatic prostate cancer.

This 2017 Movember-PCF Challenge Grant has funded our latest research developing new treatments for treatment-resistant advanced prostate cancer. More details on the grant and research it supports can be found here.
In past years, Movember-funded grants have supported our research in the following areas:

  • Blood tests that assess the tumor’s circulating DNA to predict reasons for treatment resistance.
  • Circulating tumor cell (CTC) tests to predict which patients are more or less likely to respond to hormonal therapy or chemotherapy.
  • Assessing the genome of initial tumors in the prostate compared to advanced, treatment resistant tumors.
  • Evaluating inflammation in adipose (fat) tissue around the prostate, which is associated with tumor growth.

Throughout the month of November, staff and physicians at Weill Cornell Medicine and NewYork-Presbyterian will be growing mustaches, exercising and raising funds for the Movember Foundation in support of our shared mission to cure cancer.

Get Involved!

  • Join our team by visiting https://moteam.co/wild-weill-cornell-mos
  • Grow a moustache and commit to going razor-free. It’s a great conversation starter to encourage friends and family members to donate to Movember.
  • Spin for a cure! Kill two birds with one stone. Get your workout in and support the Wild Weill Cornell Mos. Attend our cycling events on November 16th and 18th, with proceeds benefiting our team’s Movember fundraising goal.
  • Shave the date and celebrate the end of Movember by attending a happy hour. Stay tuned for final details including date and location.

Last year, we raised $13,000. We want to top that this year by raising $20K or more. Help us get there and remember that every dollar counts in the quest to cure cancer!