Approximately 65 % of all cancer patients, some three million newly diagnosed patients per year in the USA and Europe alone, are treated with cytotoxic agents with the objective to kill tumor cells. Unfortunately, treatment success with cytotoxic drugs is confounded by the acquisition of resistance to these drugs by some tumor cells. Consequently these resistant tumor cells grow once again, leading to disease progression, subsequent metastases and eventual end of life for the patient.
The development of RP101 represents a truly novel approach to the prevention of chemoresistance and enhancement of chemosensitivity. Through its unique interaction with heat shock protein 27 (Hsp27), RP101 has a clearly differentiated mechanism of action that has the potential to become a very promising therapeutic increasing the survival of cancer patients.
The majority of cancer patients are treated with chemotherapy. The cytotoxics given to the patient drive the growing tumor cells into a programmed cell death called apotosis. During this therapy the tumor develops resistance against its treatment. The cytotoxic drugs do not work anymore and consequently, the tumor restarts growing and eventually kills the patient:
Prevention of Chemoresistance
Co-treatment with RP101 prevents induction of this resistance. The patient continues to respond to the chemotherapy. The tumor shrinks:
Mode of Action
All cells contain heat shock proteins.
These are helpful for cure of external damage induced by heat, radiation and toxic substances. But cytotoxics kill tumor cells by toxicity. Therefore these HSPs have a contrary effect in the case of chemotherapy. They help the tumor to survive. A disaster for the patient. Cytotoxics enhance the activity of HSPs, and consequently induce resistance. One of these HSPs is HSP27 which acts as the key player in case of the chemoresistance.
RP101 is able to bind to Hsp27 and can suppress its activity. Thus, chemotherapy induced resistance is prevented. The tumor shrinks:
Non-Responders
The following hypothesis is suggested for the interaction of RP101 and Hsp27, and for the possible mechanism that drives the clinical results seen to date:
Thus, RP101 can also be used for patients, which do not respond to the chemotherapy (so called "Non-Responders"):
In this case RP101 is able to bind to Hsp27 and suppress its activity:
RP101 is the first small molecule known to bind to the heat shock protein Hsp27 and to modulate its effect.
Hsp27 is known to control the following cellular key functions:
Resistance against treatment with cytotoxic drugs
Development of metastases
Prevention of apoptosis
Figure: Modulation of apoptotic pathways by Hsp27. At the mitochondrial level, Hsp27, through Bid inhibits the mitochondrial release of pro-apoptotic proteins. At the postmitochondrial level, Hsp27 binds to cytochrome c resulting in the inhibition of apoptosome formation and thereby prevention of caspase activation and apoptosis. Hsp27 can also interact with and inhibit Daxx apoptotic pathway.
Interaction of Hsp27 and Pro-caspase-3 has been described as well .
Pancreatic cancer is one of the most lethal of all human cancers. Because incident and mortality for pancreatic cancer are nearly identical, either measure can be used to study the frequency of this neoplasm. Pancreatic cancer is worldwide responsible for 227,000 deaths per year, and is the eighth most common cause of death from cancer in both sexes combined, a relative position higher than for incidence (thirteenth) because of the very poor prognosis (the M/I ratio is 98%). The sex ratio is close to one. Most cases and deaths (61%) occur in developed countries, where incidence and mortality rates are between 7 and 9 per 100,000 in men and 4.5 and 6 per 100,000 in women, with lower rates in developing countries.
Early detection of pancreatic cancer is difficult, and most patients have metastatic or unresectable disease at the time of diagnosis. Patients with unresectable pancreatic cancer have a median survival of only 6 months, and 98% of patients with pancreatic cancer die from this disease.
Single agent gemcitabine is currently the standard of care for the treatment of advanced or metastatic adenocarcinoma of the pancreas. However, treatment with this agent results in only moderate improvement in survival. Therefore, several clinical trials of other anticancer agents and combination regimens have been, and continue to be, studied. The National Cancer Institute of Canada Clinical Trials Group (NCIC-CTG) recently reported the results of an international clinical trial testing the benefit of the addition of erlotinib (Tarceva™) to gemcitabine compared to gemcitabine alone for the first-line management of locally advanced/metastatic pancreatic cancer. This study demonstrated statistically significant improvement in median overall survival favoring the erlotinib arm (6.37 months for the combination vs. 5.91 months for single agent gemcitabine); the 1-year survival also favored the combination (24% vs 17%). On November 2, 2005, FDA approved Tarceva in combination with gemcitabine for first-line treatment of patients with locally advanced, unresectable or metastatic pancreatic cancer. Several other agents failed to influence overall survival when added to gemcitabine in similar randomized clinical trials; e.g. oxalyplatin and bevacizumab. Given the very modest clinical benefit of erlotinib and the failure of other tested agents to enhance survival when added to gemcitabine in this population, there remains substantial unmet medical need for better therapies.
A number of reports have described the growing recognition of Hsp27 in multiple pathologies and there has been a concurrent, exponential increase in the search for drugs that modulate the activity of this target. However the discovery of such drugs is made challenging by the fact that the tri-dimensional structures of human Hsp27 is still unknown.
RP101 is the first small molecule known to bind to Hsp27 and to modulate its effect.
RP101 is given as co-treatment to chemotherapy.
RP101 is no competitor to chemotherapeutics.
It is no competitor to any drug on the market - it enlarges the market.
Efficiency
RP101 + gemcitabine appear to be some 10 fold more effective in pancreatic cancer patients than Tarceva + gemcitabine.
The competitors: Tarceva (Erlotinib) phase III study. Result of comparison: RP101 is ten times more effective than Tarceva:
The Figure shows the comparison of effects: Probability of survival according to Kaplan-Meier.
Left: Red line = Tarceva co-treatment group; green line = chemotherapy alone group;
Right: Red line = RP101 co-treatment group; black line = chemotherapy alone group.
Every step presents a deceased patient, every -x- a living patient.
The dashed line shows the median survival of the patients.
The green lines (bottom) represent the enhancement of median survival either by Tarceva (14 days) or by RP101 co-treatment (148 days).
Other observations of our studies are:
RP101 + gemcitabine appears to be some fivefold more effective in patients with metastatic disease than gemcitabine alone.
RP101 + gemcitabine + cisplatin appears to be some fourfold more effective in patients with metastatic disease than gemcitabine + cisplatin.
All patients respond to the co-treatment with RP101.
A strong affinity of RP101 to bind to Hsp27 has been detected (directly or indirectly). In different preclinical and clinical studies it has been shown that this interaction can modulate many of the known effects of Hsp27, suggesting the potential role of RP101 in the treatment of many different tumor types.
RP101 binds to the heat shock protein Hsp27 and inhibits its association with other proteins. These molecules (e.g. caspase 3) play a critical role in the prevention/inhibition of apoptosis in tumor cells. Deregulation of apoptosis is specific for tumor cells and has not been described in normal cells. Over-expression of Hsp27 is a mechanism of tumor cells for evasion of cytotoxic drug induced apoptosis resulting in resistance against chemotherapy. RP101 prevents this chemoresistance.
Consequently, the data of our clinical studies indicate that Gemcitabine hematotoxicity is not aggravated by co-administration of RP101. It can be concluded that observed toxicities can be attributed to the cytotoxic agent Gemcitabine. There are no additional toxicities attributable to RP101. Moreover, the quality of life (Karnofsky-Index) after the 6th or latest cycle of RP101 + chemotherapy treatment is better than before the first cycle in most cases.
Supportive evidence comes from the fact that RP101 has been used for more than 20 years in thousands of patients as virostatic drug without showing noteworthy side effects.
The following clinical studies suggest that orally administered RP101 in combination with standard chemotherapy could represent a significant advance in the treatment of metastasized and locally advanced pancreatic cancer.
First Clinical Study
13 patients with metastatic and locally advanced pancreatic cancer (9 subjects with Stage IV and 4 subjects with Stage III) were treated with gemcitabine, cisplatin and RP101. Ten subjects (77%) survived more than 1 year and after one year there were close to four times more patients who had metastatic disease at the start of therapy alive in the RP101 group compared to the chemotherapy alone control group:
Results of the first study: Probability of survival according to Kaplan-Meier.
Red line = RP101 co-treatment group;
Green line = chemotherapy (gemcitabine + cisplatin) alone group; every step presents a deceased patient.
The blue arrow shows the doubling of median survival by RP101 co-treatment.
Second Clinical Study
A 22-patient dose ranging study of RP101 in the treatment of advanced pancreatic cancer was performed at 3 sites in Germany and the results were nearly identical to those from the first study. 8 subjects (38%) survived more than 1 year (control group only 9.5%) and after one year there were close to five times more patients who had metastatic disease at the start of therapy alive in the RP101 group compared to the chemotherapy alone control group:
Results of the second study: Probability of survival according to Kaplan-Meier.
Red line = RP101 co-treatment group;
Green line = chemotherapy (gemcitabine) alone group; every step presents a deceased patient.
The blue arrow shows the doubling of median survival by RP101 co-treatment.
Several clinical studies have been conducted with RP101 tablets in oncology. In a pilot phase 1 study, 31 patients with various tumor types were treated with multiple chemotherapeutic agents and RP101. In this study with 5 tumor entities (lung, breast, ovary, pancreas) it was shown that RP101 could be combined with various cytotoxic drugs: as mono-chemotherapy-regime vinorelbin, gemcitabine, docetaxel, epirubicin; as poly-chemotherapy-regime carboplatin + gemcitabin + vinorelbine, doxorubicin + endoxan + vincristine, carboplatin + vinorelbine, carboplatin + paclitaxel, carboplatin + docetaxel, carboplatin + etoposide, carboplatin + irinotecane, cisplatin + gemcitabine, epirubicin + endoxan.
This study was extended to treat 13 patients with advanced pancreatic carcinoma (Stage III and IV). In an open label study, patients received gemcitabine + cisplatin + RP101 (500 mg/day) in 5-day cycles.
A dose ranging study of RP101 and gemcitabine was completed at three sites in Germany. In this study, 22 patients were treated with a fixed dose of gemcitabine (1000 mg/m2 for 3 days) and varying doses of RP101 (500-1000 mg/day) for 12 days of a 28 day cycle.
Food effect studies with healthy volunteers showed that it is profitable not to eat immediately before taking RP101 tablets.
A phase II/III study with 153 pancreas cancer patients is currently running worldwide in 55 sites.
RP101
