Modelos de cáncer de próstata con PC-3: un modelo, cuatro aplicaciones

AUTHOR:

Sheri Barnes, PhD | Director, Scientific Development

DATE:

Mayo de 2019

Prostate cancer is the second most common type of cancer in men, with 1 in 9 men being diagnosed in their lifetime at a mean age of 66. In 2019, prostate cancer is estimated to have 174.650 new diagnoses and 31.620 patient deaths. Prognoses are very good for patients in which disease is detected early, with a five-year survival of nearly 100 %. However, many patients are asymptomatic until advanced stage disease, leaving limited treatment options due to lymph node and bone metastasis. Five-year survival decreases drastically to 30 % for patients diagnosed with advanced stage disease, so predictive preclinical models and new treatments are essential for long term survival of these patients.

Covance offers several methods of modeling prostate cancer. PC-3 is a hormone-independent human prostate tumor model that can be employed in four different ways depending on the research goal. Whether using PC-3 for subcutaneous or peritibial implantation, or using the luciferase enabled PC-3M-Luc-C6 for orthotopic or intracardiac modeling, this versatile model offers the opportunity to explore treatments in the context of local or metastatic disease.

Subcutaneous and Peritibial Modeling

Perhaps the most straightforward way to assess activity against the PC-3 model is through subcutaneous implant into the flank of male nude mice. This model is reliable and responsive to docetaxel, a standard of care for prostate cancer (Figure 1).

Fig. 1: Mean tumor growth of subcutaneous PC-3.
Fig. 1: Mean tumor growth of subcutaneous PC-3.

 

While modeling by subcutaneous implant in the flank is rapid and cost-effective, it may be best suited for early drug development. In the subcutaneous space, PC-3 is not afforded tumor-stromal interactions; therefore, it may not be as predictive as other methods. Also, the primary PC-3 tumor does not metastasize following a flank implant, so it is not appropriate for investigations into prevention of metastasis in prostate cancer progression.

Peritibial implantation is a method to determine tumor progression by caliper measurements while also assessing associated bone damage. Using this method, the cells are implanted between the ankle and knee between the tibia and fibula. The rate of tumor growth in the peritibial space is similar to subcutaneous growth in the flank (Figures 1 & 2A). However, CT imaging can also be used to longitudinally assess bone damage and recovery (Figure 2B).  This approach is useful not only from the standpoint of monitoring anti-tumor response, but also for development of agents to treat low bone density or bone damage due to metastasis. 

 

Peritibial Growth of PC-3 and Bone CT Imaging

Fig. 2A: Peritibial growth of PC-3.
Fig. 2A: Peritibial growth of PC-3.

Fig. 2B: Bone CT imaging.
Fig. 2B: Bone CT imaging.

 

Orthotopic and Metastatic Modeling

The PC-3M-Luc-C6 model, by virtue of its luciferase tag, allows for longitudinal monitoring of disease by bioluminescence imaging (BLI). This model is ideal for studies investigating response of orthotopic or metastatic disease upon treatment of a drug candidate. 

To initiate PC-3M-Luc-C6 as an orthotopic model, cells are surgically implanted into the prostate gland, and a signal in that location demonstrates established disease within two weeks of implant (Figure 3). Animals will succumb to disease between Days 50 and 65 post implant, which enables at least six weeks of dosing. In late stage disease following orthotopic implant, abdominal distension is common (~50-90 %) due to fluid accumulation in the abdominal space. Metastasis within the peritoneal space, including liver, spleen, intestine, and abdominal wall can also occur in a small number of animals (30 %), but bone metastasis has not been recorded as a result of orthotopic prostate implantation.

 

Tumor Progression Following Orthotopic PC-3M-Luc-C6 Implant

 

Fig 3A: Quantification of PC-3M-C6 following orthotopic implant.
Fig 3A: Quantification of PC-3M-C6 following orthotopic implant.

Fig. 3B: Representative BLI images.
Fig. 3B: Representative BLI images.

 

Metastasis to the bone is a major challenge in treating advanced prostate cancer. To address this unmet need, Covance has developed an induced bone metastasis model of PC-3M-Luc-C6 in which cells are injected directly into the left ventricle of the heart (intracardiac implant). This injection technique allows for homing to bone which produces detectable signal in the long bone and mandible within 7-10 days. This signal is used for staging of treatment groups, and disease progression is monitored with BLI throughout the duration of the study (Figure 4). As with other modeling discussed herein, disease initiated through intracardiac implant of PC-3M-Luc-C6 responds well to docetaxel (Figure 4B), but regrowth occurs in bone well before the subcutaneous tumor, which speaks to differential responses depending on location of disease. This model is useful for testing investigational agents against systemic disease and particularly against bone metastasis.

Tumor Progression Following PC-3M-Luc-C6 Intracardiac Implant

 

Fig. 4A: Quantification of PC-3M-C6 following intracardiac implant.
Fig. 4A: Quantification of PC-3M-C6 following intracardiac implant.

Fig. 4B: Representative BLI images.
Fig. 4B: Representative BLI images.

The PC-3 and PC-3M-Luc-C6 models offer several approaches by which to target prostate cancer. Whether a quick assessment of test agent activity through subcutaneous or peritibial modeling, or the more in-depth bioluminescence imaging of PC-3M-Luc-C6 via our orthotopic or intracardiac models, Covance is well equipped to help you explore modeling of prostate cancer using multiple approaches and modalities.

Our scientists are available to discuss using PC-3, PC-3M-Luc-C6, or one of our other models for your next project. Click here to learn more.

 


 

Note: Studies were performed in accordance with applicable animal welfare regulations in an AAALAC-accredited facility