For more than a century, the American Association of Cancer Research (AACR) has held its annual meeting, and this weekend will kick off the 101st event in Washington, DC, which is being held April 17-21, 2010. Many pharmaceutical and biotechnology companies will be presenting new data and approximately 6,300 abstracts will be discussed in oral and poster presentations.
While a comprehensive preview of AACR is beyond the scope of this article, we note that two companies working in the area of cyclin-dependent kinase [CDK] inhibition made headlines in the months leading up to AACR. Further evidence of interest in the area is demonstrated by the fact that the 2001 Nobel Prize in Physiology or Medicine was awarded for the discovery of CDKs and cyclins and the complete description of cyclin and cyclin-dependent kinase mechanisms.
By selectively interrupting the cell cycle regulation in cancer cells, inhibition of CDKs represents a promising strategy for cancer therapy. Accordingly, with more than 50 abstracts related to CDK inhibition scheduled for presentation at this year’s AACR annual meeting, we provide an overview of the target and highlight some of the companies and programs being discussed.
Each time a cell divides it undergoes a series of events collectively known as the cell cycle. Controlled and regulated cellular division is a normal part of cell physiology.
Cancer is characterized by uncontrolled cellular division and growth, which can be caused by mutations in DNA resulting in the overexpression of cancer-promoting oncogenes or repression of tumor suppressor genes. There are many examples of oncogenes and tumor suppressor genes, but some of the more common ones include signaling proteins [PI3K], receptors [HER2], and DNA damage and repair regulating proteins that control cell cycle check-points such as p53 and BRCA.
CDKs are a group of signaling kinases that play a direct role in the regulation and progression of the cell cycle. CDK activity is dependent on the availability of their regulatory subunits called cyclins, which CDKs phosphorylate in order to stop cell cycle progression in cancerous cells. Production and destruction of cyclins are tightly regulated in coordination with cell cycle progression. Targeting CDK/cyclin macromolecular complexes is an attractive strategy for the design of novel anticancer drugs.
There are over a dozen known CDK/cyclin complexes. The most extensively studied subtypes are CDK2/cyclin E, CDK2/cyclin A, CDK7/cyclin H, and CDK9/cyclin T which are key components of the p53 pathway and CDK4 and CDK6 interacting with cyclin D1, which are key components of the retinoblastoma or Rb pathway.
Many tumor mutations interfere or deregulate the tight control of cyclin-CDK interactions leading to overactive CDKs, resulting in continuous cellular proliferation or unscheduled re-entry into the cell cycle. In addition, deregulated CDK activity can result in genomic and chromosome instability, a feature observed in many advanced or aggressive tumors.
First generation, pan-CDK inhibitors have not demonstrated improved clinical outcomes. Reasons for early failures include non-specific drug targets or suboptimal dosing and scheduling. Also, pan-CDK inhibitors may not have an acceptable pharmacological window due to high toxic side effects or limited efficacy.
For example, CDK7, CDK8, and CDK9 play a role in DNA transcription. While it may be advantageous to target these CDK/cyclins as part of a multikinase drug profile, strong inhibition may result in the broad disruption of transcription, which is not desirable.
This may have been the case with BMS-387032 [subsequently known as SNS-032], a small molecule cell-cycle modulator that targets CDKs 1, 2, 4, 7, and 9. The compound demonstrated significant safety risks in Phase I studies conducted by Bristol-Myers Squibb (BMY), including increases in certain phases of the cardiac cycle, known as the QT interval.
In 2005, Sunesis Pharmaceuticals, Inc. (SNSS) acquired rights to BMS-387032 for an up-front payment of $8 million in Sunesis’ stock, future milestone payments totaling $78 million, and royalties on net sales. However, in December 2008, Sunesis notified Bristol-Myers that the company was terminating the license agreement for SNS-032 after no responses demonstrating efficacy were observed in a Phase I trial.
Next generation CDK inhibitors target select CDK sub-types and have shown improved potency along with other drug-like properties. The various CDK sub-types are active at different points within the cell cycle and discrete cancers are dependent on specific CDK sub-types. Therefore, each CDK inhibitor sub-type may be relevant to different tumors or genetic mutations.
For example, CDK4 is frequently deregulated in glioblastoma and CDK2 activity is commonly altered in colon cancer. Recently published evidence implicates certain cyclins and in particular cyclin E, the partner of CDK2, as a mediator of acquired resistance in several cancers, such as lung and breast cancer. Some of these next-generation programs are highlighted below [also see Table 1]:
Pfizer, Inc. (PFE)
In late March 2010, Pfizer made headlines with a preclinical study published in the journal Cancer Research. Results from the study demonstrated that PD-0332991, a drug being developed by Pfizer, could arrest the growth of glioblastoma multiforme [GBM] in animals. PD-0332991 is an oral agent that inhibits certain CDKs, mainly CDK4 and CDK6. Six abstracts related to PD-0332991 are scheduled for presentation at AACR. Pfizer is managing and funding all clinical development of PD-0332991, which the company licensed from Onyx Pharmaceuticals, Inc. (ONXX). PD-0332991 is the subject of various clinical trials in multiple myeloma, NHL, mantle-cell lymphoma, glioblastoma and breast cancer.
Cyclacel Pharmaceuticals, Inc. (CYCC)
Cyclacel Pharmaceuticals, which is developing a clinical stage CDK inhibitor candidate, also made headlines earlier this year. The company’s oral compound seliciclib [CYC202 or R-roscovitine], inhibits CDK2/E, CDK2/A, CDK7/H, and to a lesser degree CDK9/T. Seliciclib is currently in Phase IIb clinical trials for non-small cell lung cancer [NSCLC] and nasopharyngeal cancer.
Shares of Cyclacel Pharmaceuticals jumped from $1 to more than $4 in January 2010 when independent investigators published data in the peer-reviewed journal Clinical Cancer Research showing that both seliciclib and a second-generation CDK inhibitor from Cyclacel reversed resistance to lung cancer cells with K-Ras or N-Ras mutations. Cancers with Ras-activating mutations are thought to be among the most difficult to treat and are not responsive to modern targeted drug therapy, such as EGFR inhibitors. The data also showed that lung cancer cells are addicted to cyclin E/CDK2. Cyclacel expects to report top line results from its APPRAISE NSCLC Phase IIb trial with seliciclib later this year.
A different investigator group also recently published data in the peer-reviewed journal Clinical Cancer Research demonstrating that seliciclib reversed resistance to the aromatase inhibitor Femara® [letrozole]. Seliciclib killed hormone receptor-positive breast cancer cells that had become insensitive to the effects of letrozole because of over expression of low molecular weight Cyclin E.
At AACR, Cyclacel is introducing a second-generation CDK product candidate, which is currently in investigational new drug [IND]-directed development. The undisclosed molecule is a second generation oral CDK inhibitor with increased potency. Three abstracts related to both seliciclib and the second-generation compound are scheduled for presentation at AACR.
Sanofi-Aventis SA (SNY)
Sanofi-Aventis is developing its lead CDK inhibitor, flavopiridol [HMR-1275, alvocidib] for the treatment of both solid and hematologic malignancies. Flavopiridol is a pan–CDK inhibitor that blocks CDK9, -2, -4, and -6 at nanomolar concentrations. Published data from flavopiridol clinical trials suggest that its main toxicities are induction of neutropenia and secretory diarrhea. Phase II studies of flavopiridol as a single agent have been completed in metastatic melanoma, endometrial adenocarcinoma, and multiple myeloma demonstrating limited efficacy as a monotherapy. However, flavopiridol has shown promise as a combination therapy, with the best responses observed in CLL patients in combination with fludarabine and cyclophosphamide. Four abstracts related to flavopiridol are scheduled for presentation at AACR.
Merck & Co., Inc. (MRK)
Merck is developing its lead CDK inhibitor, SCH 727965 [dinaciclib], for multiple indications including solid tumors, NHL, multiple myeloma, ACL, and ALL. SCH 727965 is an intravenously-delivered CDK1, CDK2, CDK5, and CDK9 inhibitor. The drug is administered by a 2-hour IV infusion once every 21 days. Merck is currently recruiting patients for a Phase II study evaluating SCH 727965 to determine the activity of SCH 727965 in patients with breast cancer and in patients with lung cancer compared to standard treatment, capecitabine and erlotinib respectively. One abstract regarding the activity of SCH 727965 in cell lines for childhood cancers is scheduled for presentation at AACR.
Bayer will introduce its CDK inhibitor, BAY 1000394, in an abstract scheduled for presentation at AACR. BAY 1000394 is a nanomolar pan-CDK inhibitor targeting CDK1/Cyclin B, CDK2/Cyclin E, CDK4/Cyclin D1, and CDK9/Cyclin T1. The maximum tolerated dose for BAY 1000394 was found to be 2.0 mg/kg on QD schedule and 2.5 mg/kg on a BID intermittent schedule. BAY 1000394 is being tested in a broad range of histological tumor subtypes.
Tragara Pharmaceuticals (private)
Tragara Pharmaceuticals is developing TG02 [also known as SB1317], an oral multi-kinase inhibitor that targets CDK 1, 2, 7 and 9, as well as two other kinases – JAK2 and FLT3. TG02, which was licensed from S*BIO Pte Ltd in January 2009, is being prepared for IND filing in Q2 2010 with plans to proceed in hematology and solid tumors. Tragara recently received a $1 million grant form the Multiple Myeloma Research Foundation [MMRF] to fund the early-stage drug development TG02 in treating multiple myeloma. One abstract regarding the activity of TG02 in leukemia cell lines is scheduled for presentation at AACR.
CDKs play a pivotal role in a cell’s entry into division; de-regulated CDK activity is a well-documented player in tumor progression and represents an attractive therapeutic anti-cancer option. However, first generation CDK inhibitors have not demonstrated improved clinical outcomes. Next generation CDK inhibitors, such as those being discussed at AACR, are CDK sub-type specific and have shown improved potency along with other drug like properties. In addition, next generation CDKs are demonstrating their importance in several difficult to treat cancers, such as those dependent on Ras-activating mutations.
Table 1: Abstracts for CDK Inhibitors at AACR
Compound Abstract #/poster#: Title Date/Time PD-0332991 25: PD 0332991, a selective CDK 4/6 inhibitor, preferentially inhibits growth of ovarian cancer cells with high Rb and low p16 [CDKN2A] expression Sun, Apr 18, 1:00 PM – 3:30 PM 1758/1: Preclinical assessment of using [18F]FLT-PET imaging as a surrogate proof-of-mechanism biomarker for early drug development candidates Mon, Apr 19, 9:00 AM – 12:00 PM 3887/20: Reversible inhibition of CDK4/CDK6 sensitizes hematological tumor cells for cytotoxic killing by inducing sequential G1 arrest and synchronous S phase entry that enhances the intrinsic apoptosis pathway Tue, Apr 20, 2:00 PM – 5:00 PM 3888/21: Therapeutically activating the RB pathway in breast cancer: Key mechanisms of response and failure Tue, Apr 20, 2:00 PM – 5:00 PM 3884/17: Beta-2 spectrin opposes the CDK4-mediated suppression of TGF-beta signaling by rescuing Smad3 nuclear localization Tue, Apr 20, 2:00 PM – 5:00 PM 5047/26: Synergistic anti-cancer activity of the CDK4/6 inhibitor PD-0332991 in combination with 5-fluorouracil-based chemotherapy in human colon cancer cells Wed, Apr 21, 8:00 AM-11:00 AM Seliciclib & 2nd generation compound 22: Cyclin E amplification, a novel mechanism of resistance to trastuzumab in HER2 amplified breast cancer Sun, Apr 18, 1:00 PM – 3:30 PM 3886/19: Therapeutic potential of CDK inhibitors in MLL leukemias Tue, Apr 20, 2:00 PM – 5:00 PM 4431/20: A novel derivative of the Cdk inhibitor roscovitine that induces apoptosis in CLL and overcomes stromal cell-mediated protection Tue, Apr 20, 2:00 PM – 5:00 PM Flavopiridol 575/10: A subset of small cell lung cancer [SCLC] cell lines are Mcl-1-dependent and undergo apoptosis in response to Flavopiridol-mediated inhibition of cyclin-dependent kinase [cdk] 9 Sun, Apr 18, 2:00 PM – 5:00 PM 667/4: Mechanisms underlying synergistic interactions between the CDK inhibitor flavopiridol [Alvocidib] and the BH3 mimetic GX15-070 [Obatoclax] in human multiple myeloma cells Sun, Apr 18, 2:00 PM – 5:00 PM 650/17: Response prediction to a multitargeted tyrosine kinase inhibitor by profiling serine/threonine kinase activity and inhibition Sun, Apr 18, 2:00 PM – 5:00 PM 3544/19: Assessment of chemo-response in cells derived from patients with malignant ascites Tue, Apr 20, 9:00 AM – 12:00 PM SCH 727965 5266/20: Pediatric Preclinical Testing Program [PPTP] evaluation of the CDK inhibitor SCH 727965 Wed, Apr 21, 8:00 AM – 11:00 AM BAY 1000394 3883/16: Pharmacologic profile of the oral novel pan-CDK inhibitor BAY 1000394 in chemosensitive and chemorefractory tumor models Tue, Apr 20, 2:00 PM – 5:00 PM TG02 2542/29: TG02, a novel multi-kinase inhibitor with potent anti-leukemic activity Mon, Apr 19, 2:00 PM – 5:00 PM
Table 1: Abstracts for CDK Inhibitors at AACR